Flavonoid derivatives

ABSTRACT

The present invention provides thiazolidinediones which are useful as antiproliferative, antiinflammatory and antiinfective agents. These compounds are useful for the treatment of certain endocrine diseases including diabetes, certain malignant and non-malignant proliferative diseases including prostate cancer, breast cancer, psoriasis, and acne, certain cardiovascular disorders including hypertension and occlusive vascular diseases.

BACKGROUND OF THE INVENTION

Peroxisome proliferator-activated receptors (PPARs) are members of thenuclear receptor superfamily of ligand-activated transcription factors.Three subtypes of PPARs have been cloned from the mouse and human: i.e.,PPARα, PPARγ and PPARδ. The PPARs are believed to play a role in theregulation of lipid metabolism. They can be activated by fatty acids andhave been shown to regulate the expression levels of binding proteinsand enzymes involved in fatty acid oxidation.

It has previously been discovered that a certain class ofthiazolidinediones are selective PPARγ agonists. (see, Willson et. al.,J. Med. Chem (1996) 39:665-668). Thiazolidinediones are a class of oralinsulin-sensitizing agents that improve glucose utilization withoutstimulating insulin release. For instance, U.S. Pat. No. 4,287,200discloses certain thiazolidine derivatives having the ability to lowerblood glucose sugar levels. In addition, U.S. Pat. No. 4,572,912discloses thiazolidinedione derivatives having the ability to lowerblood lipid and blood sugar levels. These compounds were shown to havethe ability to decrease the levels of blood lipid peroxides, bloodtriglycerides and blood cholesterol.

Moreover, U.S. Pat. No. 5,338,855 discloses thiazolidine derivativescontaining a quinone moiety. These compounds were shown to have theability to reduce insulin resistance in the peripheral tissues andpossess the ability to suppress hepatic gluconeogenisis in the liver.

In addition to being anti-diabetic agents which can lower theconcentration of glucose and lipids in the blood, U.S. Pat. No.5,594,015 discloses thiazolidine derivatives as being effective in thetreatment of hyperproliferation of epithelial cell conditions, such aspsoriasis.

The anti-diabetic effect of the thiazolidinediones and their PPARγagonist activity has implicated PPARγ as the molecular target for theanti-diabetic effects of thiazolidinediones. PPARγ is predominatelyexpressed in adipose tissue and has been implicated as a masterregulator of adipocyte differentiation in pre-adipose cell lines.

In view of the role PPARγ plays in regulation of lipid metabolism andthe antagonistic behavior of thiazolidinediones, there remains a need inthe art for new thiazolidinedione derivatives and more effectivetherapies for diabetes and other ailments. As such, the presentinvention fulfills these and other needs.

SUMMARY OF THE INVENTION

The present invention provides new thiazolidinedione derivatives. Assuch, in one aspect, the present invention provides compounds of FormulaI: ##STR1## In Formula I, Y is a heteroatom including, but not limitedto, sulfur, selenium or oxygen. X, in Formula I, is a heteroatomincluding, but not limited to, oxygen, selenium sulfur or NR⁶, whereinR⁶ is a functional group including, but not limited to, hydrogen andoptionally substituted (C₁ -C₁₀)alkyl. R¹, R², R³ and R⁴, in Formula I,are functional groups which can be the same or different and include,but are not limited to, hydrogen, hydroxy, halogen, optionallysubstituted (C₁ -C₆)alkyl, optionally substituted (C₁ -C₂₀)alkoxy, (C₁-C₆)alkylcarbonyl, (C₁ -C₂₀)alkenyl, R²⁴ R²³ N(CH₂)_(x) CH(OH)(CH₂)_(y)O--, optionally substituted aroyl, or aryl(C₁ -C₁₀)alkylcarbonyl. R, inFormula I, is a functional group including, but not limited to,hydrogen, phenyl, 3,4-dihydroxyphenyl or R¹¹. R¹¹, of Formula I, is afunctional group including, but not limited to, --A--NR¹³ R¹⁴,--CONHR¹⁵, --A--S--R¹⁶ or --COOR¹⁷, where A is a lower alkylene group.In Formula I, R¹³ and R¹⁴ are functional groups which can be the same ordifferent and include, but are not limited to, hydrogen, (C₁ -C₆)alkyl,cycloalkyl or a sulfur- and a nitrogen-containing 5- or 6-memberedheterocyclic ring, where the heterocyclic ring may be optionallysubstituted by one or two hydroxyl groups. In an alternative embodiment,R¹³ and R¹⁴ together with the nitrogen to which they are bound, form apyrrolidine, piperidine or morpholine ring. R¹⁵, in Formula I, is afunctional group including, but not limited to, hydrogen, or optionallysubstituted (C₁ -C₆)alkyl. R¹⁶, in Formula I, is a functional groupincluding, but not limited to, (C₁ -C₆)alkyl or a sulfur- and nitrogencontaining 5- or 6-membered heterocyclic ring, where the heterocyclicring may be optionally substituted by one or two hydroxyl groups,carboxyl groups, or (C₁ -C₆)alkoxycarbonyl groups. R¹⁷, in Formula I, isa functional group including, but not limited to, an optionallysubstituted (C₁ -C₆)alkyl. R²³, in Formula I, is a functional groupincluding, but not limited to, hydrogen or optionally substituted (C₁-C₆)alkyl. R²⁴, in Formula I, is a functional group including, but notlimited to, phenyl, benzyl, and R²⁵ (CH₂)_(s) CH(T)(CH₂)_(k), or aheterocyclic ring having the formula: ##STR2## In an alternativeembodiment, R²⁴, R²³ and the nitrogen atom to which they are bound forma 5- or 6-membered heterocyclic ring having the formula ##STR3## R²⁵, inFormula I, is a functional group including, but not limited to, phenoxyor unsubstituted, monosubstituted, or disubstituted Ar, where Ar is anaromatic system including, but not limited to, phenyl, pyridinyl,furanyl, thiophenyl, naphthyl, where each substituent of monosubstitutedAr is the same or different and includes, but is not limited to,hydroxy, (C₁ -C₆)alkoxy, or O(CH₂)_(r) CO₂ R²³, each substituent ofdisubstituted Ar is independently hydroxy or (C₁ -C₆)alkoxy. Q, inFormula I, is a functional group including, but not limited to, SO₂, S,or O. In Formula I, the index "x" is an integer from 1 to 5; the index"y" is an integer from 1 to 5; the index "h" is an integer from 1 to 2;the index "k" is an integer from 1 to 7; the index "r" is an integerfrom 1 to 2; and the index "s" is a integer from 0 to 6. T, in FormulaI, is a functional group including, but not limited to, hydrogen or OH.Z, in Formula I, is a functional group including, but not limited to,CH₂, O, NH, NCH₃, and ##STR4## In Formula I, the index "q" is an integerfrom 0 to 1; the index "n" is an integer from 0 to 5; the index "t" isan integer from 0 to 1; the index "m" is an integer from 0 to 2; theindex "p" is an integer from 0 to 1; the index "z" is an integer from 0to 1; provided that (1) at least one of x and y is one and (2) s plus ktotal no more than 7.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising a compound of the Formula I, wherein Y, X, NR6,R¹, R², R³ and R⁴, R, R¹¹, A, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²³, R²⁴, R²⁵, A,Q, x, y, h, s, k, r, s, T, Z, q, n, t, m, p and z have the same meaningas defined above, or a pharmaceutical acceptable salt or solvatethereof, and a pharmaceutical acceptable carrier.

In yet another aspect, the present invention relates to a method oftreating a PPARγ mediated disease, comprising administering atherapeutically effective amount of a compound of the of the Formula Ito an individual suffering from a PPARγ mediated disease. In otheraspects, this invention provides methods for synthesizing the compoundsof Formula I.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates compounds of the present invention and potentialintermediates in the synthesis of compounds of the present invention.

FIG. 2 Panel A illustrates a prior art synthesis scheme. Panel Billustrates an alternative synthesis scheme to generate intermediates ofthe present invention.

FIG. 3 Panel A illustrates selective alkylation of rutin. Panel Billustrates linkage of the flavone with thiazolidinedione.

FIG. 4 illustrates a protection scheme for a flavone moiety.

FIG. 5 illustrates a synthesis scheme for compounds of the presentinvention.

FIG. 6 Panel A illustrates a synthesis scheme for compounds of thepresent invention. Panel B illustrates acid hydrolysis of a compound ofthe present invention.

FIG. 7 Panel A illustrates a synthesis scheme for an intermediatecompound of the present invention. Panel B illustrates a synthesisscheme for a compound of the present invention.

FIG. 8 Panel A illustrates intermediate compounds of the presentinvention. Panel B illustrates compounds of the present invention andintermediate compounds of the present invention.

FIG. 9 illustrates a synthesis scheme for a compound of the presentinvention.

FIG. 10 Panel A illustrates a synthesis scheme for a compound of thepresent invention. Panel B illustrates a synthesis scheme for a compoundof the present invention.

FIG. 11 Panel A illustrates compounds of the present invention. Panel Billustrates compounds of the present invention. Panel C illustratescompounds of the present invention.

FIG. 12 Panel A illustrates intermediate compounds of the presentinvention. Panel B illustrates a synthetic scheme for compounds of thepresent invention.

FIG. 13 Panel A illustrates compounds of the present invention. Panel Billustrates compounds of the present invention.

FIG. 14 Panel A illustrates compounds of the present invention. Panel Billustrates intermediate compounds of the present invention.

FIG. 15 illustrates a synthesis scheme for compounds of the presentinvention.

FIG. 16 illustrates compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

I. Glossary

As used herein, the term "alkyl" denotes branched or unbranchedhydrocarbon chains, such as, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tertbutyl, octa-decyl and 2-methylpentyl.These groups can be optionally substituted with one or more functionalgroups which are attached commonly to such chains, such as, hydroxyl,bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio,heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl,nitro, amino, alkoxyl, amido, and the like to form alkyl groups such astrifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl,carboxymethyl, cyanobutyl and the like.

The term "lower" herein means a linear or branched chain of 1 to 6carbon atoms. Hence, "lower alkyl radicals" represent linear or branchedalkyl groups of 1 to 6 carbon atoms, illustrative examples includingmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tertpentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl; 1-ethylpropyl, hexyl, isohexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and1-ethyl-1-methylpropyl.

The term "alkylene" or "lower alkylene radicals" refers to a divalentalkyl as defined above, such as methylene (--CH₂ --), propylene (--CH₂CH₂ CH₂ --), chloroethylene (--CHClCH₂ --), 2-thiobutene --CH₂ CH(SH)CH₂CH₂, 1-bromo-3-hydroxyl-4-methylpentene (--CHBrCH₂ CH(OH)CH(CH₃)CH₂ --),methylethylene, trimethylene, 1-propylene, 2-propylene, tetramethylene,1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene,1-ethylethylene, 2-ethylethylene, pentamethylene,1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene,4-methyltetramethylene and hexamethylene and the like.

The term "alkenyl" denotes branched or unbranched hydrocarbon chainscontaining one or more carbon-carbon double bonds.

The term "alkynyl" refers to branched or unbranched hydrocarbon chainscontaining one or more carbon-carbon triple bonds.

The term "aryl" denotes a chain of carbon atoms which form at least onearomatic ring having preferably between about 6-14 carbon atoms, such asphenyl, naphthyl, and the like, and which may be substituted with one ormore functional groups which are attached commonly to such chains, suchas hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano,cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl,carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the liketo form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl,anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl,methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl,trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl,amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl,imidazolylmethylphenyl, and the like.

The term "acyl" denotes the --C(O)R group, wherein R is alkyl or aryl asdefined above, such as formyl, acetyl, propionyl, or butyryl.

The term "alkoxy" denotes --OR--, wherein R is alkyl. The term "loweralkoxy radicals" there may be mentioned linear and branched alkoxygroups of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, secbutoxy, tert-butoxy, pentyloxy,isopentyloxy, hexyloxy and isohexyloxy groups.

The term "amido" denotes an amide linkage: --C(O)NR-- (wherein R ishydrogen or alkyl).

The term "amino" denotes an amine linkage: --NR--, wherein R is hydrogenor alkyl.

The term "carboxyl" denotes --C(O)O--, and the term "carbonyl" denotes--C(O)--.

The term "carbonate" indicates --OC(O)O--.

The term "carbamate" denotes --NHC(O)O--, and the term "urea" denotes--NHC(O)NH--.

The term "EC₅₀ " refers to the concentration of a compound required toactivate 50% of the receptors that bind the compound present in a sampleor a subject. Thus, in the present invention, the EC₅₀ of a PPARγmodifier is the concentration of the modifier that activates 50% of thePPARγ present in the sample or organism. The term "activate" has itsordinary meaning, i.e., cause to function or act.

The term "peroxisome proliferator activating receptor-gamma" or "PPARγ"refers to either the γ₁, γ₂ or γ₃ isotypes or a combination of allisotypes of PPARγ. PPARs are nuclear receptors which naturally bind tofatty acids and which have been implicated in adipocyte differentiation(Perlmann & Evans, Cell 90:391-397 (1997)).

The term "unit dosage form" refers to physically discrete units suitableas unitary dosages for human subjects and animals, each unit containinga predetermined quantity of active material calculated to produce thedesired pharmaceutical effect in association with the requiredpharmaceutical diluent, carrier or vehicle. The specifications for theunit dosage forms of this invention are dictated by and dependent on (a)the unique characteristics of the active material and the particulareffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active material for use in humans and animals.Examples of unit dosage forms are tablets, capsules, pills, powderpackets, wafers, suppositories, granules, cachets, transdermal patches,liposomes, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials,aerosols with metered discharges, segregated multiples of any of theforegoing, and other forms as herein described.

II. Thiazolidinedione Compounds and Synthesis

This invention provides flavonoid thiazolidine, oxazolidine andα-substituted carboxylic acid derivatives with antiproliferative,antiinflammatory, antidiabetic, and antiinfective properties, and theiruse in the treatment of proliferative (malignant and nonmalignant),inflammatory, cardiovascular, endocrine, and viral diseases in human andvertebrate animals. As such, in one aspect, the present inventionrelates to a compound of Formula I: ##STR5## wherein Y, X, NR⁶, R¹, R²,R³ and R⁴, R, R¹¹, A, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²⁴, R²⁵, A, Q, x, y, h,s, k, r, s, T, Z, q, n, t, m, p and z have the same meaning as definedabove.

In one preferred embodiment, Y is a heteroatom, such as S and O; X is O,S or NR⁶, wherein R⁶ is hydrogen or optionally substituted (C₁-C₆)alkyl; R is hydrogen or 3,4-dihydroxyphenyl; R¹ and R³ are eachhydroxy; R² and R⁴ are each hydrogen; q is an integer from 0 to 1; n isan integer from 0 to 5; t is an integer from 0 to 1; m is an integerfrom 0 to 2; p is an integer from 0 to 1; and z is 0.

With reference to FIG. 1, the attachment of an alkyl chain to theflavone moiety of target compounds 1-5, requires no fundamentalmodification to the aromatic ring system. It is believed that theantioxidant effects of the flavones are dependent upon the free phenolicoxygen atoms, as well as the heterocyclic ring: the 4H-1-chromanone.When the 3-hydroxy group of quercitin (6, R is H) is functionalized,such as in rutin (6, R is rutinose, a deoxy mannopyrano-glucoside), theantioxidant effect is retained. Two major approaches to the5-benzylic-1,3-thiazolidine-2,4-dione ring system have been reported,one of which is described in U.S. Pat. No. 4,572,912 (see, FIG. 2A). Theother has been outlined more recently (see, Hulin B. et al., J. Med.Chem. 1992; 35(10): 1853-1864 and Wilson T. et al., J. Med. Chem. 1996;39(3): 665-668).

The approach outlined in FIG. 2A was cumbersome and thus researchersprepared euglycemic agents containing the thiazolidinedione ring systemby exceptionally mild Aldol condensation of thiazolidinedione itself toa benzaldehyde 13 (see, FIG. 2B). The resultant arylidenethiazolidinediones 14 can then be reduced catalytically over Pd on Cwith hydrogen, or by the action of sodium-mercury amalgam to afford thedesired ring systems 15. Not only is the approach outlined in FIG. 2Bmore direct than the earlier method, it employs milder condition thusavoiding potential side-reactions. For example, intermediate 9 hasseveral aromatic C-H positions that are available for coupling to adiazonium intermediate during the aryl diazonium decomposition whichleads ultimately to 10.

With reference to FIG. 3A, in order to alkylate the C-3 portion of theflavone moiety, it is possible to take advantage of the naturaloccupance of bioflavanoids such as rutin 6 (where R is a disaccharide),wherein C-3 is essentially already "blocked". The additional hydroxylgroups present on the C-3-sugar moiety do not present a problem becausethe hydroxy groups of a sugar are alcoholic, with pK_(a) values in therange of 18, while the phenolic groups have pK_(a) values as low as 9.Thus, a clear acidity difference makes selective deprotonation of thephenolic hydroxyls possible. Selective alkylation of rutin has beendescribed previously as shown in FIG. 3A.

Preparation of the hydroxyethoxy derivative of quercitin is effected byphenoxide opening of ethylene oxide (see, He H. et al., Yiyao Gongye1987; 18(5): 205-206). Thus, both rutin and chloroethanol react withsodium hydroxide. Rutin 6 gives the phenoxide anion, while chloroethanolundergoes intramolecular S_(N) 2 reaction to afford oxirane (ethyleneoxide). The phenoxide anion then opens the highly reactive oxirane togive 16 where R is CH₂ CH₂ OH. Removal of the disaccharide by acidichydrolysis provides 17 (see, FIG. 3A). Application of this concept torutin, with modification of the nature of the R groups in 17, hasprovided a clean route to the flavonoid portion of target compounds 1-5.

With reference to FIG. 3B, linkage of the flavone with thethiazolidinedione system proceeded as illustrated. After linkage givesthe modified flavone 18, removal of the acetal protecting group, Aldolcondensation and reduction provide the protected target compounds 19.Deprotection afforded the desired targets 1-5.

With reference to FIG. 4, a straightforward protection scheme for theflavone system is illustrated which involves O-methylation of thephenolic groups. Tetramethylation of rutin 6 to furnish 20 is possibleupon exposure of rutin to dimethylsulfate and sodium carbonate to giveafter mild acid-catalyzed hydrolysis, 3', 4', 5, 7-tetramethoxyflavone21. Methyl protection was chosen because deprotection of anisoles toprovide phenols has been studied extensively, and there are at leasteighteen different removal methods reported in Green (see, Green T etal., Protective Groups in Organic Synthesis, 2nd ed. New York: JohnWiley & Sons, Inc., 1991).

In one preferred embodiment, the present invention relates to compoundsof Formula I, wherein Y is S; R is 3,4-dihydroxyphenyl; q is 1; n is 1to 5; t is 0; m is 0; p is 0; z is 0; R¹ and R³ are each hydroxy; and R²and R⁴ are each hydrogen; (see, FIG. 1).

The synthesis of compounds of the foregoing embodiment is set forth inFIG. 5. As illustrated therein, treatment of 21 with base (e.g., NaH)followed by an appropriate chloromethyl ether sets in place the tetheredspecies (23). Attack by an thioalkane anion of adequate steric bulk willallow for selective removal of the less hindered methyl moieties, andprovide the phenolic aldehyde 24. If the acetal of the aromatic ringproves resistant to organo-sulfide anion, then a second mild acidhydrolysis step can be undertaken to arrive at 24. With the benzaldehydein hand, its conversion to a thiazolidinedione follows readily, withmild Aldol-like condensation of thiazolidinedione itself with 24 willfurnish 25. Reduction of 25, without an adverse effect on the chromanonering system is likely under mild conditions previously employed withsodium-mercury amalgam. Several alternatives exist for this reduction,including, but not limited to, Pd/C. Thus, it is also possible to reduce25 using catalytic hydrogenation over Pd/C. If this can be accomplishedwithout reduction of the chromanone ring, then alternative protectionschemes become available, such as benzyl protection.

With reference to FIG. 6A, an alternative synthetic scheme to generate 1is illustrated. As illustrated therein, a free aldehyde-chloromethylether (27) undergoes coupling to tetrabenzylquercetin 26. Thebenzaldehyde group is stable in these conditions as there is noenolizable (exchangeable) position in either molecule. After generationof 28, simple condensation to give the arylidene thiazolidinedione 29will be straightforward. Reduction under catalytic conditions willprovide the one carbon tether 1.

In another preferred embodiment, the present invention relates tocompounds of Formula I, wherein Y is S; R is 3,4-dihydroxyphenyl; q is1; n is 2; t is 0; m is 0; p is 0; z is 0; R¹ and R³ are each hydroxy;and R² and R⁴ are each hydrogen; (see, FIG. 7B).

With reference to FIG. 7B, the synthesis of the two-carbon tether 2 isillustrated. The chemistry is similar to that used in the synthesis of1, with some practical differences relating to various experimentaldetails such as, reaction times and solvents, but also to the lack ofaldehyde group protection. The O-alkylation of 33 will occur more slowlythan the chloromethyl ether 27. However, the existence and thealkylation of aldehyde 33 with phenoxides has previously been described.(see, Nate H. et al., Chem. Pharm. Bull. 1987; 35(6): 2394-2411).

Alternatively, protection of the halo-benzaldehydes can be accomplishedusing methanol and trimethylorthoformate in the presence of a weakammonium based acid. It is possible to modify the synthetic schemeoutlined in FIG. 7B by utilizing acetal 36 (see, FIG. 7A) instead of 33.An additional step is added to deblock the ketal to arrive at 34. Thissynthesis is straightforward due to the presence of the para oxygenatom.

In another preferred embodiment, the present invention relates tocompounds of Formula I, wherein Y is S; R is 3,4-dihydroxyphenyl; q is1; n is 3-5; t is 0; m is 0; p is 0; z is 0; R¹ and R³ are each hydroxy;and R² and R⁴ are each hydrogen; (see, FIG. 1).

As illustrated in FIG. 8A, the reported benzaldehydes wherein n is 3-5have been reported. For instance, aldehyde 27 has been described alongwith 33. The three-carbon side chain, 37, was prepared much in the samemanner as the other bromides: i.e., alkylation of the dihaloalkane withthe anion of p-hydroxybenzaldehyde (see, Schweizer E. et al., J. Org.Chem. 1969; 34(1): 207-212). The four carbon aldehyde was prepared in1989 by Ito S. (see, Japanese Patent No. 01,117,867). The ortho-analogof 39 was also prepared, (see, Nate H. et al., Chem. Pharm. Bull. 1987;35(6): 2394-2411). Using these methods, the generation of benzaldehydes37, 38 and 39 is possible. Using the same reaction sequence asillustrated in FIG. 7B, compounds 3, 4 and 5 can be made.

In yet another embodiment, the present invention relates to compounds ofFormula I, wherein Y is O; R is 3,4-dihydroxyphenyl; n is 1 to 5 q is 0;t is 0; m is 0; p is 0; z is 0; R¹ and R³ are each hydroxy; and R² andR⁴ are each hydrogen; (see, FIG. 8B).

With reference to FIG. 8B, it is possible to synthesize versions of 1 byreplacing one of the acetal oxygens with carbon, such as in structure 40or 41. As shown in FIG. 9, compound 40 can be synthesized in a mannersimilar to that outlined previously. Alkylation of a4-(2-haloethyl)benzaldehyde acetal such as in 43, withtetrabenzylquercetin 26 will lead to formation of the protected tether44. Purification and deprotection of the aldehyde group with mild acidwill provide an intermediate benzaldehyde, of structure similar to 28 or34, which will then undergo Aldol-like condensation to give thearylidene thiazolidinedione 45. Finally, simultaneous double bondreduction and benzyl group deprotection will furnish the alternatetarget 40 (see, FIG. 9). It follows that homologous acetals can be usedin this scheme to arrive at other tether lengths, and will providestructures such as 41 (see, FIG. 8B).

The addition of polar atoms in the tether could have several desirableeffects including enhanced polarity for water solubility. As such, thepresent invention relates to compounds of Formula I, wherein R is3,4-dihydroxyphenyl; q is 1; n is 2 t is 1; m is 2; p is 0; z is 0; R¹and R³ are each hydroxy; and R² and R⁴ are each hydrogen. (see, FIG.10A). In one embodiment, X is preferably oxygen.

An additional ethylene-glycol like unit can be added to 2 to furnish ananalog resembling 5, the triether 47 (see, FIG. 10A). By minormodifications to the outlined schemes, it is possible to derive 47 fromcommercially available 2-bromoethyl ether (BrCH₂ CH₂ OCH₂ CH₂ Br) andthe anion of para-hyroxybenzaldehyde. After generating adduct 46,coupling it to the tetrabenzyl ether 26 will proceed as expected to givethe intermediate 47. The desired target 48 will become available asillustrated in FIG. 10A.

In addition, the present invention relates to compounds of Formula I,wherein R is 3,4-dihydroxyphenyl; q is 1; n is 2; X is NR⁶, wherein R⁶ amember selected from the group consisting hydrogen and optionallysubstituted (C₁ -C₆)alkyl; t is 1; m is 2; p is 0; z is 0; R¹ and R³ areeach hydroxy; and R² and R⁴ are each hydrogen. (see, FIG. 10B).

To generate these compounds, a simple modification to the scheme asshown in FIG. 10 is possible. The corresponding chloroethylamines areavailable and will work in place of bromethyl ether. With reference toFIG. 10B, reaction of the phenolic aldehyde with a weak base andnitrogen mustard will readily undergo rapid O-alkylation to give 49.This material is not expected to be stable under basic conditions thusit will be possible to add the anion of 26 directly to the reactionmixture to obtain 50 in a one-step operation. After generation of 50,following the scheme set forth in FIG. 5 will allow for conversion totarget 51. It is also possible to engineer other atoms in this schemesuch as X is S, S═O or SO₂, as well as longer tethering lengths and saltforms such as ammonium or sulfonium ions.

III. Thiazolidinedione Analogs

While the bulk of literature precedent exists for the thiazolidinedionesas described above, it is possible to replace the sulfur moiety (Y is S)with another heteroatom such as oxygen i.e., Y is O. Oxazolidinedionesare known to be pharmacologically similar to thiazolidinediones (see,Heitzmann, T. et al., Arzneimittelforschung 1995: 45(12), 1284-1288. andTurnbow, M. A. et al., Endocrinology 1995; 136(4), 1450-1458.) Inaddition, Y can be selenium, (Y is Se). (see, "Biochemistry ofSelenium", by R. J. Shamberger, Plenum Press, pp 273-279 and Comrie etal., J.Pharn. Pharacol., 16: 268-272 (1964)).

As such, in another embodiment, the present invention relates tocompounds of Formula I wherein Y is O; R is H; q is 1; t is 0; n is 1 to5; m is 0; p is 1; z is 0; R¹ and R³ are each hydroxy; and R² and R⁴ areeach hydrogen (see, FIG. 11A). In this embodiment, the oxazolidinedioneshave the structures 52 through 56 (see, FIG. 11A), by analogy to thethiazolidinediones 1-5, and can in fact be accessed from another classof potential PPARγ agonists, the corresponding α-hydroxy, α-thioalkoxyor α-alkoxy carboxylic acids or carboxylate esters 57-61 (FIG. 11B).

While it is possible that the enantiomers of 52-56 might undergoepimerization in vivo, the corresponding acids and acid esters 57-61will not be stereochemically labile. It is in fact possible to developan enantiospecific route to the analogs 57-61, hence leading toenantiomerically pure 52-56.

Synthesis of 57-61, allows for production of the oxazolidinediones 52-56by treatment with NaOEt and urea, or alternatively by condensation withguanidine followed by hydrolysis, thus providing for a convergent routeto these analogs (see, FIG. 11C) (see, Lednicer, D. et al., OrganicChemistry of Drug Synthesis. John Wiley and Sons, Inc., N.Y., 1977.Chapter 5, pp 232-234.)

The α-hydroxyacids corresponding to 57 -61 can be generated in chiralform by diazotization of an alkylated tyrosine. With reference to FIG.12A, when phenylalanine 62 is reacted with nitrous acid the resultantα-hydroxyacid 64 retains the original stereochemistry as a consequenceof a double inversion via intermediate 63. Further, the oppositestereoisomer 66 is obtained by a S_(N) 2 reaction of a sulfonylderivative 65 with acetate ion (see, Coppola, G. et al., AsymmetricSynthesis, Construction of Chiral Molecules Using Amino Acids. JohnWiley and Sons, Inc., N.Y., 1987. Chapter 2.1, pp 45-46.)

With reference to FIG. 12B, diazotization can be carried out under basicconditions by reaction first with a alkyl nitrite to avoid ringnitrosation. The tethered amino acid 67 (wherein R is a protectedflavone) will provide alcohol 68 which will be inverted to the otherenantiomer as shown. Finally, either enantiomer of 68 will provide theoxazolidinediones 52-56. Thus, upon esterification of 68, ethyl ester 69can then either be inverted as discussed above to furnish 70 or canitself be taken on to give the oxazolidinedione 72. Likewise, 70 canthen also provide the enantiomeric oxazolidinedione 71. Deprotection ofeither as described above by hydrogenolysis will give the final products52-56 in either enantiomer as desired.

The esters 70 or 69 will hydrogenolyzed directly to give thecorresponding carboxylate alcohols 57 through 61. The ester can be leftin place to serve as a prodrug, or will be removed by hydrolysis withbase.

The tethered tyrosine derivative 67 will be accessible from a protectedversion of tyrosine commonly employed in peptide synthesis, i.e.,N-tBOC-tyrosine tert-butyl ester 73 (see, FIG. 13A). Upon phenoxideformation of 73 and O-alkylation with the corresponding dihalide asoutlined for the aldehydes 27, 33, and 37-39, formation of 74 will beevidenced. After coupling as described previously with the protectedflavone, 26, a protected target 75 is accessible. To afford a finalproduct directly, hydrogenolysis of 75 under acidic conditions willeffect both benzyl group cleavage as well as BOC and t-Bu ester removal.

Alternatively, simple acid treatment will leave the flavonoid portionprotected as 76 which will be diazotized (as in FIG. 12A) to obtain theX-R is OH series, thus providing access to 57-61 in both NH₂ and OHclasses. Either 57 -61 with XR is OH or NH₂ will be used to generate thecorresponding heterocycles such as the oxazolidinediones or even theimidazolinediones wherein XR is NH₂.

As was the case for the thiazolidinediones, the acids andoxazolidinediones can be linked via heteroatoms such as O, S or N. Withreference to FIG. 13B, the preparation of targets such as 77 or 78 aresynthesized utilizing chemistry outlined herein. In 77, Y can be O or Nand R₁ in the case of O is an electron pair, but in the case of N can beany alkyl or aryl group or other functionality containing carboncompound. In 78, Z is O, N or S and in the cases of N and S, R₁ can beany alkyl or aryl group or other functionality containing carboncompound. The R₂ group can be a simple ester to promote bioavailabilitysuch as an ethyl ester which should be cleaved in vivo to the free acid(R₂ is H). In either of these structures, X is O, S or N and in thelatter case, N would have an R group that could be any alkyl or arylgroup or other functionality containing carbon compound.

IV. ALTERNATIVE FLAVANOIDS

Other antioxidants or natural products can be tethered by similarmethods to the thiazolidinedione, oxazolidinedione or α-substitutedcarboxylic acids. Additional flavonoids which can be used according tothe invention, include, but are not limited to, taxifolin, catechin,genistein, epicatechin, eriodictyol, naringenin, troxerutin, chrysin,tangeretin, luteolin, epigallocatechin and epigallocatechin gallate,fisetin, kaempferol, galangin, gallocatechin and epicatechin gallate.

Of particular interest are isoflavones including, but not limited to,genistein. In these cases the tether takes a different format. As such,in another embodiment, the present invention relates to compounds ofFormula I, wherein R is H; q is 1; t is 1; n is 2; m is 2; p is 1; z is0; R¹ and R³ are each hydroxy; and R² and R⁴ each hydrogen (see, FIG.14A).

With reference to FIG. 14A, a normal alkyl chain attached to an oxygenatom already present in the isoflavone portion of the target compounds79-83 requires no fundamental modification to the aromatic ring system.The antioxidant effects of the isoflavones are dependent upon the freephenolic oxygen atoms of the heterocyclic 4H-1-chromanone ring system.When the 4'-hydroxy group of genistein 6 is functionalized as in thetargets 79-83, the antioxidant effect will be retained.

One approach to these compounds makes use of the methods outlined inFIG. 2B. Since the isoflavone ring system is synthesized in two stepsfrom simple precursors, preparation of a protected version of 84, suchas 88, by synthesis from simple precursors is possible. For example,Nair et al., Chang, Y. et al., J. Agric. Food Chem. 1994; 42:1869-1871.) have shown that 4-hydroxyphenylacetic acid 86 can undergo aphenol acylation in a manner analogous to the Houben-Hoesch reactionusing microwave radiation, but with vast improvement to yield and easeof synthesis, to provide genistein 84 as illustrated in FIG. 14B.Alternatively, an analogous one pot synthetic procedure has beenpublished (see, T. Hase, et al., J. Chem.Perk. Trans. I. 3005, 1997).

With reference to FIG. 14B, an alternatively protected version of 84,namely 88, is possible by any number of pre-existing methods (see,Baker, W. et al., J. Chem. Soc. 1953; 1852-1862), or by starting withdibenzyloxyphenol instead of 85 and will be expected to provide 88instead of 84. After the synthesis of the protected form of genistein88, linkage gives the modified isoflavone 90, removal of the acetalprotecting group, Aldol condensation and reduction will provide theprotected target compounds 91. (see, FIG. 15) Deprotection will thenafford the desired targets 79-83.

With reference to FIG. 16, the tether attachment to the benzaldehydering can be via carbon or oxygen (92, 93) heteroatoms can be insertedinto the tether itself to give hybrid structures such as 94 and/or 95with head groups of either thiazolidinediones, oxazolidinediones, andα-substituted carboxylates or carboxylate derivatives such as esters oramides.

Additional flavonoids and isoflavanoids will be useful in practicing thepresent invention. As such, in another aspect, the present inventionrelates to compounds of Formula I wherein the isoflavonoid isrepresented by Formula II ##STR6## wherein R¹¹ is a member selected fromthe group consisting of --A--NR¹³ R¹⁴, --CONHR¹⁵, --A--S--R¹⁶ and--COOR¹⁷, wherein A denotes a lower alkylene group; R¹³ and R¹⁴ aremembers independently selected from the group consisting of hydrogen,(C₁ -C₆)alkyl, cycloalkyl and a sulfur- and a nitrogen-containing 5- or6-membered heterocyclic ring, where the heterocyclic ring may beoptionally substituted by one or two hydroxyl groups, or, alternatively,R¹³ and R¹⁴ together with the nitrogen to which they are bound form apyrrolidine, piperidine or morpholine ring; R¹⁵ is a member selectedfrom the group consisting of hydrogen and optionally substituted (C₁-C₆)alkyl; R¹⁶ is a member selected from the group consisting of (C₁-C₆)alkyl and a sulfur- and nitrogen containing 5- or 6-memberedheterocyclic ring wherein said heterocyclic ring may be optionallysubstituted by one or two hydroxyl groups, carboxyl, or (C₁-C₆)alkoxycarbonyl groups; R¹⁷ is optionally substituted (C₁ -C₆)alkyl.

In one aspect, the modified isoflavone of Formula II will be used togenerate a compound of Formula I, similarly as discussed above with 88,and then tethered as shown in FIG. 15. Removal of the acetal protectinggroup, Aldol condensation and reduction will provide the protectedtarget compounds with the flavone being Formula II (see, FIG. 15).Deprotection will then afford the desired target of Formula I having anflavone moiety of Formula II.

Although the attachment of thiazolidinedione moiety to the isoflavone ofFormula II is preferably as outlined in FIG. 15, those of skill in theart will appreciate that the synthetic schemes can be modified toaccommodate various functionality at R¹¹. For instance, when R¹¹ is--CONHR¹⁵, and R¹⁵ is hydrogen, the amino group will need to beprotected and deprotected to generate the compound of Formula I. Variousprotection groups are available for amino groups such as carbamates andamides. (see, Green T et al., Protective Groups in Organic Synthesis,2nd ed. New York: John Wiley & Sons, Inc., 1991).

Isoflavones of Formula II and their synthesis are described in detail inU.S. Pat. No. 4,841,077. Briefly, for compounds having the radical--A--NR¹³ R¹⁴, a 2-methylisoflavone derivative is brominated usingN-bromosuccinimide in carbon tetrachloride to generate the2-bromo-methylisoflavone and subsequent reaction with various amineswith the 2-bromo-methylisoflavone. The carboxamide compounds representedby Formula II wherein --CONHR¹⁵ can be prepared by reaction of ammoniaor an amine with a carboxylic acid derivative of an isoflavone. Thesubstituted thio-lower-alkyl-isoflavone derivatives represented byFormula II wherein --A--S--R¹⁶, can be prepared by reaction of ahalogeno-lower-alkyl-isoflavone derivative with a thiol or an alkalimetal salt thereof. The compounds represented by Formula II wherein--COOR¹⁷ can be prepared by esterification or ester exchange reactionbetween a carboxylic acid, a salt, an ester or a reactive derivativethereof with a substituted or unsubstituted alkanol of or a reactivederivative thereof.

Flavone derivatives of Formula II can prepared by cyclization reactions.Of various types of cyclization reaction of a 2,4,6-trihydroxyα-phenyl-acetophenone derivative with an acid halide or acid anhydrideto form an isoflavone derivative is the most preferred because thesubstituent at position 2 can be simultaneously introduced.

In yet another aspect, this invention relates to compounds of Formula Iwherein the flavonoid moiety is represented by Formula III ##STR7##wherein R²¹ is 3,4 dihydroxyphenyl; R²³ is hydrogen or optionallysubstituted (C₁ -C₆)alkyl; R²⁴ is phenyl, benzyl or R²⁵ (CH₂)_(S)CH(T)(CH₂)_(k), or a heterocyclic ring having the formula ##STR8## oralternatively, together with R²³ and the nitrogen atom to which they arebound form a 5- or 6-membered heterocyclic ring having the formula##STR9## R²⁵ is either phenoxy or unsubstituted, monosubstituted, ordisubstituted Ar, wherein, Ar is a member selected from the groupconsisting of phenyl, pyridinyl, furanyl, thiophenyl, naphthyl, eachsubstituent of monosubstituted Ar is a member selected from the groupconsisting of hydroxy, (C₁ -C₆)alkoxy, and O(CH₂)_(r) CO₂ R₂₃, eachsubstituent of disubstituted Ar is independently hydroxy or (C₁-C₆)alkoxy; Q is a member selected from the group consisting of SO₂, S,or O; x is an integer from 1 to 5; y is an integer from 1 to 5; h is aninteger from 1 to 2; k is an integer from 1 to 7; r is an integer from 1to 2; s is a integer from 0 to 6; T is either hydrogen or OH; Z is amember of the group consisting of CH₂, O, NH, NCH₃, and ##STR10## q isan integer from 0 to 1; n is an integer from 0 to 5; t is an integerfrom 0 to 1; m is an integer from 0 to 2; p is an integer from 0 to 1; zis an integer from 0 to 1; provided that (1) at least one of x and y isone and (2) s plus k total no more than 7.

The synthesis of flavones of Formula III are described in detail in U.S.Pat. No. 4,889,941. Briefly, these compounds can be generated byreacting a flavone compound with a ω-haloolefin in the presence of abase such as sodium or potassium hydroxide, potassium carbonate, orpiperidine, and a solvent such as an alcohol of 1-4 carbon atoms,acetone, dimethylformamide, or dimethylsulfoxide, to give a flavoneolefin. This flavone olefin is allowed to react with peroxides such asm-chloroperbenzoic acid or peracetic acid in a suitable solvent such aschloroform, methylene chloride or acetic acid, to produce an epoxide.Treatment of this epoxide with various amines in an alcoholic solvent of1-4 carbons at a suitable temperature, or in the presence of a Lewisacid such as triethylaluminum in methylene chloride yields a product ofFormula III.

Preferably, compounds of Formula III will be used to generate compoundsof Formula I using the procedures similar to those illustrated in FIG.5, wherein the attachment of thiazolidinedione moiety to the flavone ofFormula III is via the hydroxyl group at C-3. Those of skill in the artwill appreciate that the synthetic schemes as previously outlined can bemodified to accommodate various side-chain functionalities at R²³ andR²⁴. Protective groups will be required at reactive sites to temporarilyblock their reactivity. These groups will then be removed to generatethe compounds of Formula I after the coupling of the thiazolidinedionemoiety to the flavone of Formula III.

In another aspect, this invention relates to compounds of Formula Iwherein the flavone is represented by Formula IV ##STR11## in which: A',C' and D', independently of one another, represent H, OH or OCH₃ ; B',F', G' and J', independently of one another, represent H, OH, OCH₃ or--OCH₂ --CH₂ --OH, with the proviso that at least two of the radicals A'to G' or J' represent OH. The compounds of formula IV are known (see,U.S. Pat. No. 4,431,912). They can be obtained in particular accordingto the processes described in "The Flavonoids", Harborne J. B., Mabry T.J., Helga Mabry, 1975, pages 1 to 45.

Preferably, compounds of Formula IV will be used to generate compoundsof Formula I using the procedures similar to those illustrated in FIG.5, wherein the attachment of thiazolidinedione moiety to the flavone ofFormula IV is via the hydroxyl group at C-3. Those of skill in the artwill appreciate that the synthetic schemes as previously outlined can bemodified to accommodate various side-chain functionalities. Protectivegroups will be required at reactive sites to temporarily block theirreactivity. These groups will then be removed to generate the compoundsof Formula I after the coupling of the thiazolidinedione moiety to theflavone of Formula IV.

In still yet another aspect, this invention relates to compounds ofFormula I wherein the flavonoid is represented by Formula V ##STR12## inwhich R³⁰ represents: a hydrogen or a radical OR'³⁰ in which R'³⁰represents:

a) hydrogen or b) an alkyl radical containing from 1 to 10 carbon atomsin a straight or branched chain optionally substituted by one or moresubstituents selected from the group consisting of:

i) phenyl and monocyclic or bicyclic aromatic heterocyclic radicals, alloptionally substituted by one ore more substituents selected fromhalogen atoms, such as chlorine, bromine or fluorine and trifluoromethyland hydroxy radicals and alkyl and alkoxy radicals each having from 1 to5 carbons atoms in a straight or branched chain;

ii) carboxy;

iii) alkoxycarbonyl in which the alkoxy group contains from 1 to 5carbons atoms in a straight or branched chain;

iv) aminocarbonyl of the formula: --C(O)NR'³¹ and R'³² in which each ofR'³¹ and R'³² which may be identical or different, represent: a hydrogenatom, or an alkyl radical having from 1 to 5 carbon atoms in a straightor branched chain, or R'³¹ and R'³² form together with the nitrogen atomto which they are bonded a heterocyclic radical optionally containing asecond hetero atom selected from oxygen, nitrogen and sulfur, whichheterocyclic radical may be substituted by an alkyl radical having from1 to 5 carbon atoms in a straight or branched chain or by an aralkylradical, such as, for example, a benzyl radical, the aryl moiety ofwhich is optionally substituted by one or more alkyl and alkoxy radicalseach having from 1 to 5 carbon atoms in a straight or branched chain;

v) an amino radical of the formula --C(O)NR"³¹ R"³² in which each ofR"³¹ and R"³² may be identical or different, represents: hydrogen, oralkyl or hydroxyalkyl each having from 1 to 5 carbon atoms in a straightor branched chain, or R"³¹ and R"³² form together with the nitrogen atomto which they are bonded a heterocycle optionally containing anotherheteroatom: oxygen, nitrogen or sulfur,

vi) a radical --OR" in which R" represents hydrogen, an alkyl radicalhaving from 1 to 5 carbon atoms in a straight or branched chain or agroup --COA in which: A represents an alkyl radical having from 1 to 5carbon atoms in a straight or branched chain, or a radical --C(O)NR"³¹and R"³² in which R"³¹ and R"³² are as defined above, and

vii) SO₃ H and SO₃ M in which M represents an alkali metal.

c) an acyl radical of the formula: --COR'"³⁰ in which R'"³⁰ represents:an alkyl radical having from 1 to 10 carbon atoms in a straight orbranched chain, an aralkyl radical, the aryl moiety of which isoptionally substituted by one or more substituents selected from halogenatoms and hydroxy radicals and alkyl and alkoxy radicals each havingfrom 1 to 5 carbon atoms in a straight or branched chain, or an arylradical optionally substituted in the same manner as the aryl moiety ofthe aralkyl radical defined above, and d) tosyl. In addition, theirsteroisomers and also their possible addition salts with apharmaceutically acceptable acid or base.

The synthesis of flavones of Formula V are described in detail in U.S.Pat. No. 5,280,024. The synthesis of compounds of Formula V isaccomplished by condensing a phosphorane and a benzoic acid chloride.The reaction of the phosphorane and benzoic acid chloride is carried outin an especially suitable manner by operating in a suitable solvent,such as, for example, pyridine or a mixture of toluene and pyridine,while heating under reflux for approximately three hours.

Preferably, compounds of Formula V will be used to generate compounds ofFormula I using the procedures similar to those illustrated in FIG. 5,wherein the attachment of thiazolidinedione moiety to the flavone ofFormula V is via the hydroxyl group at C-3. Those of skill in the artwill appreciate that the synthetic schemes as previously outlined can bemodified to accommodate various side-chain functionalities. Protectivegroups will be required at reactive sites to temporarily block theirreactivity. These groups will then be removed to generate the compoundsof Formula I after the coupling of the thiazolidinedione moiety to theflavone of Formula V.

In other aspects, this invention relates to compounds of Formula Iwherein the flavonoid is represented by Formula VI ##STR13## wherein:R⁴¹ represents hydrogen, lower alkyl, halogen, hydroxy, loweralkylcarbonyloxy or an R⁴⁹ --O group; where R⁴⁹ represents an alkyl oralkenyl group with up to 20 carbon atoms; R⁴² represents hydrogen, loweralkyl, halogen, hydroxy, lower alkylcarbonyloxy or an R⁴⁹ --O group,wherein R⁴⁹ has the above meaning, and R⁴³ represents hydrogen, loweralkyl, halogen, hydroxy, lower alkylcarbonyloxy or an R⁴⁹ --O group,wherein R⁴⁹ has the above meaning, or two of the substituent groups R⁴¹to R⁴³ are bonded to adjacent carbon atoms and together represent analkylenedioxy group with 1 or 2 carbon atoms,

with the proviso that if more than one of the substituent groups R⁴¹ toR⁴³ represent oxygen-containing groups, these groups are identical; R⁴⁴represents hydrogen, lower alkyl, halogen, hydroxy, loweralkylcarbonyloxy or an R⁴⁹ --O group, wherein R⁴⁹ has the above meaning,and R⁴⁵ represents hydrogen, lower alkyl, halogen, hydroxy, loweralkylcarbonyloxy or an R⁴⁹ --O group, wherein R⁴⁹ has the above meaning,or R⁴⁴ and R⁴⁵ are bonded to adjacent carbon atoms and together form analkylenedioxy group with 1 or 2 carbon atoms, with the proviso that ifboth R⁴⁴ and R⁴⁵ represent oxygen-containing groups, these groups areidentical, and, if R⁴¹, R⁴² or R⁴³ represent hydroxy or loweralkylcarbonyloxy groups, oxygen-containing groups R⁴⁴ and R⁴⁵ areidentical to these groups.

The synthesis of flavones of Formula VI are described in detail in U.S.Pat. No. 4,886,806. Compounds of Formula VI will be used to generatecompounds of Formula I using the procedures illustrated in FIG. 5 above.Briefly, the flavones of Formula VIII are prepared by first lithiatingthe 3-position of a flavone by reacting the flavone withnucleophile-free organic lithium base and by treating the lithiatedintermediate product with carbon dioxide, whereby the lithium is thenreplaced by the carboxyl group. In particular, preferably lithiumdiisopropylamide or also lithium tetramethylpiperidide or lithiumhexamethyldisilazide are organic lithium bases suitable as lithiatingagents. The lithiation is carried out in a solvent which is inert underthe reaction conditions, for instance a cyclic ether such astetrahydrofuran, at temperatures between -90° C. and -50° C. Theresulting 3-lithio-flavone compounds are processed further directly intothe acids by treating the reaction solution with carbon dioxide and thenacidifying it.

Preferably, compounds of Formula VI will be used to generate compoundsof Formula I using the procedures similar to those illustrated in FIG.5, wherein the attachment of thiazolidinedione moiety to the flavone ofFormula V is via the carboxyl group at C-3. Those of skill in the artwill appreciate that the synthetic schemes as previously outlined can bemodified to accommodate various side-chain functionalities. Protectivegroups will be required at reactive sites to temporarily block theirreactivity. These groups will then be removed to generate the compoundsof Formula I after the coupling of the thiazolidinedione moiety to theflavone of Formula VI.

Preferred compounds of Formula I are set forth in Table I below.

                                      TABLE I                                     __________________________________________________________________________      #STR14##                                                                       -                                                                          cmp #                                                                              Y  q  n  X    t  m  p  z  R          R.sup.1                                                                           R.sup.2                                                                           R.sup.3                                                                           R.sup.4                 __________________________________________________________________________     1   S  1  1  --   0  0  0  0  3,4 di-hydroxyphenyl                                                                     OH  H   OH  H                          2 S 1 2 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                             3 S 1 3 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                             4 S 1 4 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                             5 S 1 5 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            40 S 0 2 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            41 S 0 3 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            48 S 1 2 O    1 2 0 0 3,4 di-hydroxyphenyl OH H OH H                          51 S 1 2 N-ethyl 1 2 0 0 3,4 di-hydroxyphenyl OH H OH H                       52 O 1 1 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            53 O 1 2 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            54 O 1 3 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            55 O 1 4 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            56 O 1 5 -- 0 0 0 0 3,4 di-hydroxyphenyl OH H OH H                            77 O 1 2 O 1 2 0 0 3,4 di-hydroxyphenyl OH H OH H                             94 O 1 2 O 1 2 1 0 hydrogen OH H OH H                                       __________________________________________________________________________

V. CHARACTERIZATION AND PURIFICATION OF THE TARGETS

The synthetic chemistry outlined above can be carried out by standardmethods apparent to those skilled in the art, and employ purification ofreaction products by chromatography and/or crystallization. Producthomogeneity can be ascertained by high performance liquidchromatography. A variety of columns (normal phase silica gel, reversephase C-18, etc.) are available, as are computer workstations to analyzethe results. Once reaction products are deemed greater than 99.5% HPLCpure, they can be analyzed by elemental analysis, NMR spectroscopy,FTIR, UV and EI or CI mass spectroscopy. Exact mass determinations willbe possible and particularly applicable to intermediates. Other physicalproperties can be determined and recorded such as solubility, meltingpoint, stability, etc. A careful study of chemical stability can beperformed and suitable formulation for the oral route of administrationcan be examined.

VI. BIOLOGICAL ASSAY

Compounds of Formula I are activators of PPARγ. As describedhereinbelow, a transient cotransfection assay can be used to screen forPPARγ antagonist. In this assay, chimeras are constructed that fuse theligand binding domains of three murine PPAR subtypes (α,γ and NUC-1) tothe DNA binding domain of the yeast transcription factor GAL4.Expression plasmids for the GAL4-PPAR chimeras are then transfected intoCV-1 cells with a reported construct containing five copies of the GAL4DNA binding site upstream of the thymidine kinase (tk) promoter drivingchloramphenicol acetyl transferase (CAT) gene expression. Using thisassay systems, compounds of Formula I which are activators of PPARγ andnot PPARα and NUC-1 are identified. (see, J. M. Lehmann et al., J. Biol.Chem. 270:12953-12956 (1995)).

Plasmids--GAL4-PPAR chimera expression constructs contain thetranslation initiation sequence and amino acids 1-76 of theglucocorticoid receptor fused to amino acids 1-147 of the yeasttranscription factor GAL4, including the DNA binding domain, in the pSG5expression vector (Stratagene). cDNAs encoding amino acids 167-468,138-440, and 174-475 of murine PPARα, NUC-1, and PPARγ1 are amplified bypolymerase chain reaction and inserted C-terminal to GAL4 in the pSG5expression vector (Stratagene) to generate plasmids pSG5-GAL4-PPARα,pSG5-GAL4-NUC-1, and pSG5-GAL4-PPARγ, respectively. The regions of thePPARs included in the chimeras should contain the ligand binding domainsbased on their homology to ligand binding domains of characterizednuclear receptors. The chimeras initially contained the translationstart site and N-terminal 262 amino acids of the glucocorticoidreceptor, including the τ₁ transcriptional transactivation domain.However, as these chimeras had high basal activity in CV-1 cells, a0.6-kilobase BglII fragment containing the τ₁ domain can be removed,leaving the translation start site and amino acids 1-76 of theglucocorticoid receptor. Wild-type receptor expression vectors can begenerated by insertion of cDNAs encoding murine PPARα, NUC-1, PPARγ1 andPPARyγ2 into the expression vector pSG5 (Stratagene). Reporter plasmid(UAS)₅ -tk-CAT can be generated by insertion of five copies of a GAL4DNA binding element into the BamHI site of pBLCAT2. The reporter aP2-tk-CAT was generated by insertion of the 518-bp EcoRI/XBAI fragmentcontaining the enhancer of the aP2 gene into the BamHI site of pBLCAT2.

Cotransfection Assay--CV-1 cells are plated in 24-well plates in DMEmedium supplemented with 10% delipidated fetal calf serum. In general,transfection mixes contain 10 ng of receptor expression vector, 100 ngof the reporter plasmid, 200 ng of β-galactosidase expression vector(pCH110, Pharmacia) as internal control, and 200 ng of carrier plasmid.Transfections can be done with Lipofectamine (Life Technologies, Inc.)according to the manufacturer's instructions. Cell extracts wereprepared and assayed for chloramphenicol acetyltransferase andβ-galactosidase activities as described previously.

Ligand Binding Assay--cDNA encoding amino acids 174-475 of PPARγ1 can beamplified via polymerase chain reaction and inserted into bacterialexpression vector pGEX-2T (Pharmacia). GST-PPARγ LBD can be expressed inBL21(DE3)plysS cells and extracts prepared as described previously. Forsaturation binding analysis, bacterial extracts (100 μg of protein) isincubated at 4° C. for 3 h in buffer containing 10 mM Tris (pH 8.0), 50mM KCl, 10 mM dithiothreitol with [³ H]-BRL49653 (specific activity, 40Ci/mmol)in the presence or absence of unlabeled BRL49653. Bound can beseparated from free radio-activity by elution through 1-ml Sephadex G-25desalting columns (Boehringer Mannheim). Bound radioactivity eluted inthe column void volume and can be quantiated by liquid scintillationcounting.

VII. COMPOSITIONS AND METHODS

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the Formula I: ##STR15## wherein Y,X, NR⁶ R¹, R² R³ and R⁴, R, R¹¹, A, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R²³, R²⁴,R²⁵, A, Q, x, y, h, s, k, r, s, T, Z, q, n, t, m, p and z have the samemeaning as defined above, or a pharmaceutical acceptable salt or solvatethereof, and a pharmaceutical acceptable carrier.

The compounds of this invention can be formulated in a variety ofcarriers and delivery systems. For instance, to prepare a long-actingdepot formulation, a therapeutically effective concentration of thecompound is placed in an oil, resin, biopolymer or other suitabledelivery device as is known in the art. The amount of the therapeuticcompound to be administered and the compound's concentration in depotformulations depend upon the vehicle or device selected, the clinicalcondition of the patient, the side effects and the stability of thecompound in the formulation. Thus, the physician employs the appropriatepreparation containing the appropriate concentration of the therapeuticcompound and selects the amount of formulation administered, dependingupon clinical experience with the patient in question or with similarpatients.

In addition to the therapeutic compound, the compositions can include,depending on the formulation desired, pharmaceutically-acceptablenon-toxic carriers, or diluents which include vehicles commonly used toform pharmaceutical compositions for animal or human administration. Thediluent is selected so as not to unduly affect the biological activityof the combination. Examples of such diluents which are especiallyuseful for injectable formulations are water, the various salinesolutions, Ringer's solution, dextrose solution, and Hank's solution. Inaddition, the pharmaceutical composition or formulation may includeadditives such as other carriers; adjuvants; or nontoxic,non-therapeutic, non-immunogenic stabilizers and the like.

Furthermore, excipients can be included in the formulation. Examplesinclude cosolvents, surfactants, oils, humectants, emollients,preservatives, stabilizers and antioxidants. Any pharmacologicallyacceptable buffer may be used, e.g., Tris or phosphate buffers.Effective amounts of diluents, additives and excipients are thoseamounts which are effective to obtain a pharmaceutically acceptableformulation in terms of solubility, biological activity, etc.

Thus, a composition of the invention includes a therapeutic compoundwhich can be formulated with conventional, pharmaceutically acceptable,vehicles for topical, oral or parenteral administration. Formulationscan also include small amounts of adjuvants such as buffers andpreservatives to maintain isotonicity, physiological and pH stability.Means of preparation, formulation and administration are known to thoseof skill. See generally Remington's Pharmaceutical Science 15th ed.,Mack Publishing Co., Easton, Pa. (1980).

To prepare a topical formulation for the treatment of dermatologicaldisorders listed in Tables II, III, IV & V, or diseases of the externaleye (Table VII), a therapeutically effective concentration of thecompound is placed in a dermatological vehicle as is known in the art.The amount of the therapeutic compound to be administered and thecompound's concentration in the topical formulations depend upon thevehicle selected, the clinical condition of the patient, the sideeffects and the stability of the compound in the formulation. Thus, thephysician employs the appropriate preparation containing the appropriateconcentration of the therapeutic compound and selects the amount offormulation administered, depending upon clinical experience with thepatient in question or with similar patients.

The concentration of the therapeutic compound for topical formulationsis in the range of about 1 mg/mL to about 1000 mg/mL. Typically, theconcentration of the therapeutic compound for topical formulations is inthe range of about 2.5 mg/mL to about 25 mg/ml. Solid dispersions of thetherapeutic compound as well as solubilized preparations can be used.Thus, the precise concentration is subject to modest experimentalmanipulation in order to optimize the therapeutic response. About 2,500mg of therapeutic compound per 100 grams of vehicle is useful in thetreatment of skin lesions to provide a 2.5% weight/weight (w/w)formulation. Suitable vehicles include oil-in-water or water-in-oilemulsions using mineral oils, petrolatum and the like as well as gelssuch as hydrogel.

Alternative topical formulations include shampoo preparations, oralpaste, and mouth wash preparations. ORABASE7 can be used as the baseoral paste to which the therapeutic compound is added. Concentrations oftherapeutic compound are typically as stated above for topicalformulations.

In yet another aspect, the present invention relates to a method oftreating a PPARγ mediated disease, comprising administering atherapeutically effective amount of compound of the Formula I: ##STR16##wherein Y, X, NR⁶, R¹, R², R³ and R⁴, R, R¹¹, A, R¹³, R¹⁴, R¹⁵, R¹⁶,R¹⁷, R²³, R²⁴, R²⁵, A, Q, x, y, h, s, k, r, s, T, Z, q, n, t, m, p and zhave the same meaning as defined above, to an individual suffering froma PPARγ mediated disease. Diseases treatable with the novel compoundsdescribed herein are outlined in Tables II, III, IV, V, VI & VII. Thesecompounds have clinical utility in the treatment of non-malignant (TableII) and malignant (Table III) diseases in multiple organ systems,diseases caused by naked or coated DNA and RNA viruses, and local anddisseminated diseases associated with the infection by these viruses(Table IV), human immunodeficiency virus (HIV) infection and diseasesassociated with HIV infection (Table V), neuro-psychiatric diseases(Table VI), and diseases of the eye (Table VII).

The methods of treatment provided by this invention are practiced byadministering to a human or vertebrate animal in need a dose of acompound of Formula I that binds to or modifies the activity ofperoxisome proliferator activated receptor-gamma (PPARγ), or apharmaceutically acceptable salt or solvate thereof. The present methodincludes both medical therapeutic and/or prophylactic treatment asnecessary.

The compounds described in this invention can be use to treat a varietyof disorders including proliferative, inflammatory, metabolic, orinfectious disorders. The specific disorders that can be treated withthe compounds described in this invention are listed in Tables II, III,IV, V, VI & VII.

Using methods of the invention, therapeutic compounds are typicallyadministered to human patients topically or orally. Parenteraladministration is used in appropriate circumstances apparent to thepractitioner. Preferably, the compositions are administered in unitdosage forms suitable for single administration of precise dosageamounts. For example long-acting depot compositions are administeredsubcutaneously or intramuscularly as precise unit doses with each doselasting weeks to months.

VIII. ADMINISTRATION

The therapeutic compound is optionally administered topically by the useof a transdermal therapeutic system (see, Barry, DermatologicalFormulations, (1983) p. 181 and literature cited therein). While suchtopical delivery systems have been designed largely for transdermaladministration of low molecular weight drugs, by definition they arecapable of percutaneous delivery. They can be readily adapted toadministration of the therapeutic compounds of the invention byappropriate selection of the rate-controlling microporous membrane.

For ophthalmic applications (Table VII), the therapeutic compound isformulated into solutions, suspensions, and ointments appropriate foruse in the eye. The concentrations are usually as discussed above fortopico-local preparations. For ophthalmic formulations, see Mitra (ed.),Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y.(1993) and also Havener, W. H., Ocular Pharmacology, C. V. Mosby Co.,St. Louis (1983).

The therapeutic compound is alternatively administered by aerosol. Thisis accomplished by preparing an aqueous aerosol, liposomal preparationor solid particles containing the compound. A nonaqueous (e.g.,fluorocarbon propellent) suspension could be used. Sonic nebulizers arepreferred because they minimize exposing the therapeutic compound toshear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of the therapeutic compound together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularcompound, but typically include nonionic surfactants (Tweens, Pluronics,or polyethylene glycol), innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

For oral administration, either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof interest is mixed into formulations with conventional ingredientssuch as talc, magnesium stearate, dicalcium phosphate, magnesiumaluminum silicate, calcium sulfate, starch, lactose, acacia,methylcellulose, and functionally similar materials as pharmaceuticaldiluents or carriers. Capsules are prepared by mixing the compound ofinterest with an inert pharmaceutical diluent and filling the mixtureinto a hard gelatin capsule of appropriate size. Soft gelatin capsulesare prepared by machine encapsulation of a slurry of the compound ofinterest with an acceptable vegetable oil, light liquid petrolatum orother inert oil. Fluid unit dosage forms for oral administration such assyrups, elixirs and suspensions can be prepared. The water soluble formscan be dissolved in an aqueous vehicle together with sugar, aromaticflavoring agents and preservatives to form a syrup. An elixir isprepared by using a hydroalcoholic (e.g., ethanol) vehicle with suitablesweeteners such as sugar and saccharin, together with an aromaticflavoring agent. Suspensions can be prepared with an aqueous vehiclewith the aid of a suspending agent such as acacia, tragacanth,methylcellulose and the like.

Appropriate formulations for parenteral use are apparent to thepractitioner of ordinary skill. Usually, the therapeutic compound isprepared in an aqueous solution (discussed below) in a concentration offrom about 1 to about 100 mg/mL. More typically, the concentration isfrom about 10 to 60 mg/mL or about 20 mg/mL. Concentrations below 1mg/mL may be necessary in some cases depending on the solubility andpotency of the compound selected for use. The formulation, which issterile, is suitable for various parenteral routes includingintra-dermal, intra-articular, intra-muscular, intravascular, andsubcutaneous.

Slow or extended-release delivery systems, including any of a number ofbiopolymers (biological-based systems), systems employing liposomes, andpolymeric delivery systems, can be utilized with the compositionsdescribed herein to provide a continuous or long term source oftherapeutic compound. Such slow release systems are applicable toformulations for topical, ophthalmic, oral, and parenteral use.

IX. ROUTES OF ADMINISTRATION

Therapeutic agents of the invention are usually delivered oradministered topically or by transdermal patches for treating disordersinvolving the skin that are listed in Tables II, III, IV, V, VI & VII.Oral administration is preferred for disorders in Tables II, III, IV, V,VI & VII that cannot be treated effectively by topical therapy.Additionally, the agents can be delivered parenterally for theconditions in listed in Tables II, III, IV, V, VI & VII, that do notrespond to oral or topical therapy or for conditions where oral ortopical therapy is not feasible. Parenteral therapy is typicallyintra-dermal, intra-articular, intramuscular or intravenous.

A preferred way to practice the invention for disorders in II, III, IV,V, & VII that affect the skin is to apply the compound of interest, in acream, lotion, ointment, or oil based carrier, directly to the skinlesions. Typically, the concentration of therapeutic compound in acream, lotion, or oil is 1-2%. Alternatively, an aerosol can be usedtopically. These compounds can also be orally administered.

In general, the preferred route of administration is oral, parenteral,or topical (including administration to the eye, scalp, and mucousmembranes). Topical administration is preferred in treatment of skinlesions, including lesions of the scalp, lesions of the cornea(keratitis), and lesions of mucous membranes where such directapplication is practical. Shampoo formulations are sometimesadvantageous for treating scalp lesions such as seborrheic dermatitisand psoriasis of the scalp. Mouthwash and oral paste formulations can beadvantageous for mucous membrane lesions, such as oral lesions andleukoplakia.

Oral administration is a preferred alternative for treatment ofdermatological and eye diseases listed in Tables II, III, IV, V, VI &VII where direct topical application is not useful, and it is apreferred route for other non-dermatological applications. Intravenousadministration may be necessary in disorders that cannot be effectivelytreated by topical or oral administration.

Intra-articular injection is a preferred alternative in cases ofarthritis (psoriatic or nonpsoriatic) where the practitioner wishes totreat one or only a few (such as 2-6) joints. Usually, the compound isdelivered in an aqueous solution of about 10-20 mg/ml. Additionally, thetherapeutic compounds are injected directly into lesions (intra-lesionadministration) in appropriate cases. Intradermal administration is analternative for dermal lesions such as those of psoriasis.

For pulmonary applications, a chemical delivery system for drugtargeting to lung tissue using a compound of Formula I as the "targetormoiety". Therefore a preferred therapeutic compound is compound 3 thatmodifies the activity of PPARγ and is formulated into solutions,suspensions, aerosols and particulate dispersions appropriate forapplication to the pulmonary system. The therapeutic agent may beinhaled via nebulizer, inhalation capsules, inhalation aerosol, nasalsolution, intratracheal as a solution via syringe, or endotracheal tubeas an aerosol or via as a nebulizer solution. In vitro kinetic and invivo pharmacokinetics studies have shown that the compounds of Formula Iprovide an effective pulmonary delivery system which, in a sufficientlystable in buffer and biological media, is hydrolyzed rapidly into therespective active parent drugs, with significantly enhanced delivery andretention of the active compound to lung tissue.

X. DOSAGE AND SCHEDULES

An effective quantity of the compound of interest is employed intreatment. The dosage of compounds used in accordance with the inventionvaries depending on the compound and the condition being treated. Theage, weight, and clinical condition of the recipient patient; and theexperience and judgment of the clinician or practitioner administeringthe therapy are among the factors affecting the selected dosage. Otherfactors include the route of administration the patient, the patient'smedical history, the severity of the disease process, and the potency ofthe particular compound. The dose should be sufficient to amelioratesymptoms or signs of the disease treated without producing unacceptabletoxicity to the patient.

Broadly, an oral dosing schedule is from about 100 to about 600 mg twicea day. More typically, a single dose is about 100-200 mg of compoundgiven twice a day. A convenient oral dose for an adult patient is 200 mgtwice a day. A dosage range for topical treatment is about 0.1% to about10% (weight/volume) in a cream or ointment, applied twice a day. A usualdose for intra-articular injection is 20-40 mg injected per joint, notgenerally exceeding three joints per therapy session. A typical dosagefor intra-dermal administration is about 20-75 mg per injection persite. A typical dosage for intravenous or intramuscular administrationin an adult patient would be between 1 mg and 1000 mg per day given insingle or divided doses depending on the judgement of the practitioner.

In some aspects, for example a thiazolidinedione, the oral dose isdetermined from the following formula:

    Oral dose (in milligrams)=(k.sub.1)(EC.sub.50)(k.sub.2)(LBW)(MW);

wherein k₁ is a dimensionless constant with values ranging from 5 to100; EC₅₀ is in mol/L;

k₂ is the fractional water content of the lean body weight (LBW) of thepatient=0.72 L/kg, (see, GEIGY SCIENTIFIC TABLES, VOL 1, Lentner (ed.),p217, Ciba-Geigy Limited, Basle, Switzerland (1981); and

MW is the molecular weight of the drug in g/mol.

Typically, the dosage is administered at least once a day until atherapeutic result is achieved. Preferably, the dosage is administeredtwice a day, but more or less frequent dosing can be recommended by theclinician. Once a therapeutic result is achieved, the drug can betapered or discontinued. Occasionally, side effects warrantdiscontinuation of therapy. In general, an effective amount of thecompound is that which provides either subjective relief of symptoms oran objectively identifiable improvement as noted by the clinician orother qualified observer.

The compounds in this invention can also be given orally in combinationwith compounds that bind or modify the activity of the vitamin Dreceptor or in combination with compounds that bind or modify theactivity of the retinoid X receptors or retinoic acid receptors toprovide for a synergistic effect in the treatment or prevention of thedisorders listed in Tables II, III, IV, V, VI & VII. Examples of suchcompounds that provide for synergistic effect when given in combinationwith the drugs encompassed by the current invention include vitamin Danalogs, various retinoic acid derivatives, and other ligands forretinoid X receptors or retinoic acid receptors including but notlimited to compounds such as LG100268, tazarotene, TTNPB, or LGD1069(Targretin).

Synergistic therapeutic effects can be achieved by oral administrationof the drugs encompassed in the current invention together with orallyor intravenously administered drugs that bind to and or modify theactivity of either the vitamin D receptor or retinoid X receptors orretinoic acid receptors. As such, in another embodiment, the presentinvention relates to a method of treating a PPARγ mediated disease,comprising administering a combination therapy of a compound of FormulaI and a member selected from the group consisting of a drug that bind toor modifies the activity of a vitamin D receptor, a retinoid X receptor,or a retinoic acid receptor.

A preferred dosage range for administration of a retinoic acidderivative or retinoid would typically be from 0.1 to 100 mg persquare-meter of body surface area, depending on the drug's ability tobind to or modify the activity of its cognate nuclear receptor, given insingle or divided doses, orally or by continuous infusion, two or threetimes per day. For synergistic therapy, the preferred dosages and routesand frequency of administration of the vitamin D analogs or retinoidcompounds can be similar to the dosages and routes and frequency ofadministration ordinarily recommended for these agents when givenwithout compounds of Formula I. Examples of effective retinoids are9-cis-retinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid(at-RA). Preferred retinoids for this purpose would include13-cis-retinoic acid, tazarotene, or Targretin. A preferred dosage rangefor systemic administration of a vitamin D analog would typically befrom 0.1 to 100 mg per square-meter of body surface area, depending onthe drug's ability to bind to and or activate its cognate vitamin Dreceptor, given in single or divided doses, orally or by continuousinfusion, two or three times per day. Examples of effective vitamin Danalogs are 1,25-dihydroxy-vitamin D (1,25-(OH)₂ -vit D) andcalcipotriene. The dosage range and routes and frequency ofadministration of compounds of Formula I required to achieve synergisticeffects when given with vitamin D or retinoid derivatives are the sameas those described elsewhere in this disclosure. The preferred mode ofadministration of these drugs for synergistic therapeutic purposes wouldbe orally although alternatively one can use topical or parenteralroutes of administration. Synergistic therapeutic effects can also beachieved for conditions that are treated by topical administration ofvitamin D derivatives or retinoid related compounds such as psoriasis,acne, or other disorders not involving the skin described in Tables II,III, IV, V, VI & VII. The dosages and the modes and frequency ofadministration of the vitamin D or retinoid related compounds forsynergistic topical therapy would be similar to those ordinarilyrecommended for these agents when given without compounds of Formula I.The dosage range and the modes and frequency required for topicaladministration of the compounds of Formula I given in combination withvitamin D or retinoid related compounds are the same as those describedelsewhere in this disclosure.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those of ordinary skill in the art that theoperating conditions, materials, procedural steps and other parametersof the system described herein may be further modified or substituted invarious ways without departing from the spirit and scope of theinvention. For example, the invention has been described with humanpatients as the usual recipient, but veterinary use is alsocontemplated.

XI. EXAMPLES

General. All reactions were carried out under an argon atmosphere withdry, freshly distilled solvents under anhydrous conditions, unlessotherwise stated. Acetone was distilled from potassium carbonate, and N,N-dimethylformamide (DMF), from calcium hydride. Yields were applied tochromatographically and spectroscopically (¹ H-NMR) homogeneousmaterials. Reagents were purchased at highest commercial quality andused without further purification unless otherwise mentioned. Reactionswere monitored by thin-layer chromatography carried out on 250 micronsAnaltech, Inc. silica gel plates, employing UV light and p-anisaldehydesolution and heat to visualize the distributions of compounds. Silicagel (60 Å, 230-400 mesh) (Whatman Inc.) was used for flash columnchromatography. Preparative thin-layer chromatography (PTLC) separationswere carried out on 1000 microns silica gel plates (Analtech). NMRspectra were obtained by Bruker Advance DXR-400 or DXR-300 instrumentsand calibrated using tetramethylsilane. Abbreviations were used toexplain multiplicities as followings: s=singlet, d=doublet, t=triplet,q=quartet, qui=quintet, m=multiplet, b=broad.

EXAMPLE 1

This example illustrates the synthesis of compound 3.

4-(3-bromopropyloxy)benzaldehyde (37) (see, FIG. 8A). K₂ CO₃ (1.82 g, 13mmol) and 1,3-dibromopropane (3.05 mL, 30 mmol) were added to a solutionof 4-hydroxy-benzaldehyde (1.22 g, 10 mmol) in acetone (30 mL). Themixture was heated under reflux for 8.5 hrs. Then the reaction mixturewas filtered and the solvent was removed by evaporation. The resultingresidue was mixed with ether and then washed consecutively with 5% NaOH,water, and brine. After drying with MgSO₄ and evaporation of thesolvent, flash column chromatography (silica gel, hexane100%>EtOAc:hexane=10:90>20:80) gave the desired compound as a paleyellow oil: Rf=0.71 (silica gel, EtOAc:hexane=35:65); yield 61%; ¹ H-NMR(300 MHz, CDCl₃) δ9.86 (1H, s), 7.82-7.79 (2H, dd, J=6.9 and 1.8 Hz),7.00-6.97 (2H, dd, J=7.1 and 1.6 Hz), 4.19-4.15 (2H, t, J=5.8 Hz),3.61-3.56 (2H, t, 6.4 Hz), 2.37-2.28 (2H, qui, 6 Hz).

5,7,3',4'-Tetra-O-benzylquercitin (26) (see, FIG. 7B). K₂ CO₃ (2.26 g,16 mmol) and benzylbromide (1.95 mL, 16 mmol) were added to a solutionof rutin (1.0 g, 1.6 mmol) in DMF (10 mL). The mixture was heated at110° C. for 11 hrs. Then the reaction mixture was filtered, and waterand EtOAc were added for extraction. 5% NaOH, water and brine were usedto wash the combined EtOAc layer. The EtOAc layer was dried with MgSO₄and the solvent was removed by evaporation. Flash column chromatography(silica gel, EtOAc:MeOH=98:2>95:5) provided solid compound 16 (R isbenzyl): Rf=0.55 (silica gel, EtOAc:MeOH=95:5). Hydrolysis of 16 (1.17g, 1.2 mmol) was carried out with CHCl₃ (37%, 20 mL), stirring at r.t.for 2 hrs. The reaction mixture was quenched with water and extractedwith EtOAc. The combined EtOAc layer was washed with water and brine,dried with MgSO₄ and removed by evaporation. Flash column chromatography(silica gel, EtOAc hexane=15:85→20:80) gave compound 26 as a yellowsolid: Rf=0.3 (silica gel, EtOAc:hexane=20:80, 1% AcOH); yield 21%; ¹H-NMR (400 MHz, CDCl₃) δ11.70 (1H, s), 7.92 (1H, s), 7.75 (1H, d, J=7.2Hz), 7.62-7.20 (20H, m), 7.00 (1H, d, J=7.1 Hz), 6.54 (1H, s), 6.44 (1H,s), 5.25 (2H, s), 5.22 (2H, s), 5.19 (2H, s), 5.10 (2H, s).

NaH (20 mg, 0.46 mmol) and 37 (92.35 mg, 0.38 mmol) were added to asolution of 26 (250 mg, 0.38 mmol) in DMF (7 mL). The reaction mixturewas stirred at r.t. for 2 hrs. Then the reaction mixture was quenchedwith ice and extracted with EtOAc. The combined EtOAc layer was washedwith water and brine, dried with MgSO₄, and removed by evaporation.Flash column chromatography (silica gel, EtOAc:hexane=30:70→40:60) gavethe intermediate 3-carbon tether aldehyde compound (see, FIG. 7B,similar to compound 34 however with a 3 carbon tether) as a light yellowsolid: R_(f) =0.24 (silica gel, EtOAc:hexane=20:80); yield 67%; ¹ H-NMR(400 MHz, CDCl₃) δ9.79 (1H, s), 7.75-7.73 (2H, d, J=8 Hz), 7.66 (1H, d,J=2 Hz), 7.59-7.57 (2H, d, J=8 Hz), 7.46-7.28 (20 Hz, m), 6.88 (1H, d,J=3 Hz), 6.86 (1H, d, J=3 Hz), 6.52 (1H, d, J=2 Hz), 6.44 (1H, d, J=2Hz), 5.25 (2H, s), 5.18 (2H, s), 5.14 (2H, s), 5.08 (2H, s), 4.19 (2H,t), 4.08 (2H, t), 2.22-2.10 (2H, m).

2,4-thiazolidinedione (56 mg, 0.48 mmol) and piperidine (4.8 μL, 0.048mmol) were added to a solution of intermediate 3-carbon tether aldehydecompound from the previous step (100 mg, 0.12 mmol) in EtOH (2 mL). Thereaction mixture was heated at 100° C. for 10 hrs in apressure-resistant container. Since the intermediate 3-carbon tetheraldehyde compound was a solid precipitation, it was filtered and washedwith EtOH. It was then applied to vacuum pump to dry completely: Rf=0.51(EtOAc:hexane=50:50); yield 36%; ¹ H-NMR (300 MHz, DMSO) δ12.4 (1H, s),7.70-7.68 (2H, d, J=6.6 Hz), 7.63-7.61 (2H, d, J=7.7 Hz), 7.51-7.31(21H, m), 7.00-6.88 (4H, m), 6.70 (1H, s), 5.23 (4H, s), 5.17 (2H, s),5.04 (2H, s), 4.12-4.09 (2H, t, J=5.6 Hz) 4.09-4.05 (2H, t, J=6.0 Hz),2.05 (2H, m).

Compound 3 is then generated with catalytic hydrogenation over Pd/C.

EXAMPLE 2

This example illustrates a clinical trial and therapy by topicalapplication.

A patient having dermal manifestations of either psoriasis vulgaris, oracne vulgaris, or human papilloma virus (HPV) infection (e.g.,anogenital warts) is selected for therapy using the invention. Acompound of Formula I that modifies the activity of PPARγ is prepared ina cream vehicle at a concentration of 1 to 5% (weight/volume), typically2.5% and is applied to the affected skin three times a day. After theskin lesions have subsided, therapy is discontinued.

EXAMPLE 3

This example illustrates a clinical trial and therapy by oraladministration.

A patient having type 2 diabetes mellitus, or chronic generalized acne,or chronic generalized psoriasis, with or without psoriatic arthritis,or rheumatoid arthritis, or inflammatory bowel disease (e.g., ulcerativecolitis) is selected for therapy. The patient weighs 80 kilograms. Forinfants or children the doses suggested are lowered in a linear fashionbased on body weight or surface area. The female patient ofchild-bearing potential is given a pregnancy test to confirm that thepatient is not pregnant. Provided that the patient is not pregnant anddoes not plan to become pregnant during treatment, a compound of FormulaI that modifies the activity of PPARγ is orally administered in a dosageof 20 to 1,000 milligrams twice daily, more typically 100 mg twicedaily. The patient is monitored for improvement in the manifestations ofthe index disease. Additionally, a complete blood count, including whitecell count and differential, a platelet count, and liver function tests(such as levels of alkaline phosphatase, lactose dehydrogenase, andtransaminases) are checked prior to treatment and periodicallythereafter. The dosage is tapered when the manifestations of the diseasesubside, or discontinued if indicated.

EXAMPLE 4

This example illustrates a clinical trial and therapy by intravenousinjection administration.

A patient having non-metastatic cancer, such as breast cancer, prostatecancer or colon cancer is selected for therapy. The patient weighs 80kilograms. For infants or children the doses suggested are lowered in alinear fashion based on body weight or surface area. The female patientof child-bearing potential is given a pregnancy test to confirm that thepatient is not pregnant. If indicated, the tumor is surgically excised.When the patient is stable post-surgically, a compound of Formula I thatmodifies the activity of PPARγ administered intravenously in a dose of50 to 1,000 mg, more typically in a dosage of 200 milligrams, as a bolusor continuous infusion over 4 hr, every 12 hr. The patient is monitoredfor improvement in his or her manifestations of the cancer in terms oflaboratory tests such as prostate specific antigen (PSA) for prostaticcancer, or carcinoembryonic antigen (CEA) for breast or colon cancer.Additionally, a complete blood count, including white cell count anddifferential, a platelet count, and liver function tests (such as levelsof alkaline phosphatase, lactose dehydrogenase, and transaminases) arechecked prior to treatment and periodically thereafter. The dosage istapered when the manifestations of the disease subside, or discontinuedif indicated.

EXAMPLE 5

This example illustrates a clinical trial and therapy by intralesionalinjection administration.

The patient is one who has venereal warts (HPV infection), ordermatological manifestations of Kaposi sarcoma (with or withoutinfection with the human immunodeficiency virus) who is not a candidatefor surgery, or in whom surgery may impair bodily functions (such aspainful sexual activity, or impairment in urination or defecation in thecase of venereal warts). The patient is treated by administering,intralesionally, injection(s) of a compound of Formula I that modifiesthe activity of PPARγ. The compound is administered in a 5 to 50 mg/mL,more typically 20 mg/mL of an aqueous solution, a suspension or anemulsion. About 10-75 mg are injected directly into each lesion,depending on its size and volume. The therapy is repeated weekly untilthe lesions are eradicated.

EXAMPLE 6

This example illustrates a clinical trial and therapy by intra-articularinjection administration.

A patient having psoriatic arthritis or rheumatoid arthritis withpainful, swollen, inflamed joints, is treated with intra-articularinjection(s) of a compound of Formula I that modifies the activity ofPPARγ. The compound is administered in a 5 to 50 mg/mL, more typically20 mg/mL of an aqueous solution, a suspension or an emulsion. About10-50 mg are injected directly into each joint, depending on the jointand the severity of the disease. The therapy is repeated weekly untilthe disease subsides and the pain and inflammation resolves.

EXAMPLE 7

This example illustrates a clinical trial and therapy by intrathecalinjection administration.

A patient having viral meningitis (e.g., meningitis caused bycytomegalovirus), is treated with intrathecal injection(s) of a compoundof Formula I that modifies the activity of PPARγ. The compound isadministered by injection or via catheter, in a 5 to 50 mg/mL (moretypically 20 mg/mL) of an aqueous solution, a suspension or an emulsion.About 10-50 mg, depending on the patient's lean body-mass and theseverity of the disease, is injected directly into the intrathecalspace. The therapy is administered 3 time a week and tapered to onceweekly as symptoms subside, and eventually discontinued when theinfectious agent is eradicated.

EXAMPLE 8

This example illustrates a clinical trial for ocular therapy by topicalapplication.

For ophthalmic applications, the therapeutic compound is a compound ofFormula I that modifies the activity of PPARγ and is formulated intosolutions, suspensions, and ointments appropriate for application to theexternal eye. The formulation contains the drug at a concentration of 20mg/mL. A patient having allergic conjunctivitis, or viralconjunctivitis, or keratitis, or uveitis is treated by topico-localadministration of the optic formulation, with 2 to 3 drops beinginstilled in each eye and the process repeated every 4 hr for 2 wk ormore, depending on the type or severity of the disease, until thesymptoms have subsided or resolved.

EXAMPLE 9

This example illustrates a clinical trial for pulmonary therapy.

The preferred therapeutic compound is 3 which modifies the activity ofPPARγ and is formulated into solutions, suspensions, aerosols andparticulate dispersions appropriate for application to the pulmonarysystem. The patient weighs 80 kilogram. For infants or children thedoses suggested are lowered in a linear fashion based on body weight orsurface area. The patient has asthma or COPD. The therapeutic agent maybe inhaled via nebulizer, inhalation capsules, inhalation aerosol, nasalsolution, intratracheal as a solution via syringe, or endotracheal tubeas an aerosol or via as a nebulizer solution. For delivery vianebulizer, the therapeutic agent is given at a dose of 0.5 to 50 mg per2 mL solution, more typically 10 mg/2 mL dose given every 15 min asneeded for acute treatment. For delivery by metered dose inhaler, thetherapeutic agent is given at a dose of 0.05 to 1.0 mg per actuation,more typically 0.2 mg per actuation, given every 4 hr.

                                      TABLE II                                    __________________________________________________________________________    Examples of non-malignant proliferative, inflammatory disorders                 treatable with compounds described in this invention                        Organ System                                                                           Disease/Pathology                                                    __________________________________________________________________________    Dermatological                                                                         Psoriasis (all forms), acne vulgaris, acne rosacea, common                    warts,                                                                  anogenital (venereal) warts, eczema; lupus associated skin lesions;                   dermatitides such as seborrheic dermatitis and solar dermatitis             ;                                                                       keratoses such as seborrheic keratoses, senile keratosis, actinic                     keratosis, photo-induced keratosis, skin ageing, including                    photo-induced skin aging, keratosis follicularis; keloids and                 prophylaxis against keloid formation; leukoplakia, lichen                   planus,                                                                 keratitis, contact dermatitis, eczenia, urticaria, pruritus,                  hidradenitis, acne inversa.                                                  Cardiovascular Hypertension, vasculo-occlusive diseases including                      atherosclerosis, thrombosis and restenosis after angioplasty;               acute                                                                   coronary syndromes such as unstable angina, myocardial                        infarction, ischemic and non-ischeinic cardiomyopathies, post-MI                      cardiomyopathy and myocardial fibrosis, substance-induced                     cardiomyopathy.                                                      Endocrine Insulin resistant states including obesity, diabetes mellitus              (types 1                                                                & 2), diabetic retinopathy, macular degeneration associated with                      diabetes, gestational diabetes, impaired glucose tolerance,                   polycystic ovarian syndrome; osteoporosis, osteopenia,                        accelerated aging of tissues and organs including Werner's                    syndrome.                                                            Urogenital Endometriosis, benign prostatic hyperplasia, leiomyoma,                     polycystic kidney disease, diabetic nephropathy.                     Pulmonary Asthma, chronic obstructive pulmonary disease (COPD),                      reactive                                                                airway disease, pulmonary fibrosis, pulmonary hypertension.                  Immunological/ Rheumatoid arthritis, Raynaud's phenomenon/disease,                   Sjogren's                                                              Connective tissue/ syndrome systemic sclerosis, systemic lupus erythemat             osus,                                                                  Joints vasculitides, ankyiosing spondylitis, osteoarthritis, reactive                  arthritis, psoriatic arthritis, fibromyalgia.                        Other Fibrocystic breast disease, fibroadenoma, chronic fatigue                        syndrome.                                                          __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________    Examples of neopiastic diseases or malignancies diseases treatable with        compounds described in this invention                                        Organ System                                                                          Malignancy/Cancer type                                                __________________________________________________________________________    Skin    Basal cell carcinoma, melanoma, squamous cell carcinoma;                 cutaneous T cell lymphoma; Kaposi's sarcoma.                                 Hematological Acute leukemia, chronic leukemia and myelodysplastic                  syndromes.                                                              Urogenital Prostatic, renal and bladder carcinomas, anogenital carcinoma            s                                                                        including cervical, ovarian, uterine, vulvar, vaginal, and those                     associated with human papilloma virus infection.                      Neurological Gliomas including glioblastomas, astrocytoma, ependymoma,                medulloblastoma, oligodendroma; meningioma, pituitary adenoma,                neuroblastoma, craniopharyngioma.                                     Gastrointestinal Colon, colorectal, gastric, esophageal, mucocutaneous              carcinomas.                                                             Breast Breast cancer including estrogen receptor and progesterone                   receptor.                                                                positive or negative subtypes, soft tissue tumors.                           Metastasis Metastases resulting from the neoplasms.                           Other Angiomata, angiogenesis associated with the neoplasms.                __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________    Examples of viral infections and related pathologies treatable with            compounds described in this invention                                        Virus     Viral infection/cancer or other virus-associated pathology          __________________________________________________________________________    HTLV      T-cell leukemia/lymphoma, HTLV-associated                              arthritides/myelopathies.                                                    HPV Cervical and anogenital cancers; common and anogenital                     (venereal) warts, including verrucae, condyloma or condyloma                  acuminata, related non-neoplastic (e.g., keratitis, conjunctivitis)                    pre-neoplastic and neoplastic (e.g., conjunctival epithelial                  neoplasms) diseases of the eye.                                     HAV, HBV, HCV Hepatitis, hepatocellular carcinoma, lymphoma.                  CMV Hepatitis, retinitis, meningitis.                                         HSV, VSV Related mucocutaneous, oropharyngeal and genital diseases,                     related skin and respiratory infections, variceila-zoster,                  chicken                                                                pox, herpes zoster, post-herpetic neuralgia, conjunctivitis,                  keratoconjunctivitis, keratitis.                                             HHV Exanthem subitum, infectious mononucleosis.                               EBV Infectious mononucleosis, chronic fatigue syndrome, lymphoma,                       conjunctivitis, keratitis, and related infections of the eye.       Adenoviruses Upper and Iower respiratory tract infections, pneumonia,                   conjunctivitis.                                                     RSV Upper and lower respiratory tract infections, pneumonla.                  PMV Mumps and related manifestations, e.g., conjunctivitis.                   MV, RV Measles, Rubella ("German measles") and related manifestations.                 Coxsackie viruses Conjunctivitis, diabetes mellitus, respirator              y infections.                                                         Influenza viruses Upper and Iower respiratory tract infections,                       pneumonia.                                                          __________________________________________________________________________     HIV, Human Immunodeficiency Virus; HTLV, Human Tcell Lymphocyte Virus;        HPV, Human Papilloma Virus; HAV, Hepatitis A Virus; HBV, Hepatitis B          Virus; HAV, Hepatitis C Virus; CMV, Cytomegalovirus; HSV, Herpes Simplex      Virus (Types I & II); HHV, Human Herpes Virus; EBV, EpsteinBarr Virus;        RSV, Respiratory Syncytial Virus; VZV, VaricellaZoster Virus; PMV,            Paramyxovirus; MV, Measles (Rubeola) Virus; RV, Rubella Virus            

                                      TABLE V                                     __________________________________________________________________________    HIV related infections and diseases treatable with compounds described         in this invention                                                                        Viral infection/manifestation or other HIV-associated                          Organ system disease                                             __________________________________________________________________________    Immunologic AIDS, primary HIV infection.                                        Dermatological Anogenital cancers including rectal and cervical cancer,        Kaposi's sarcoma, squamous cell carcinoma, hairy                              leukoplakia, molluscum contagiosum, warts (HPV                                infections), seborrheic dermatitis, psoriasis, xeroderma,                     HSV and varicella-zoster infections.                                         Hematologic Non-Hodgkin's lymphoma, B cell lymphoma, anemia,                   neutropenia, thrombocytopenia.                                               Gastrointestinal Anorexia, gastroparesis, diarrhea, malabsorption,                        gastrointestina1 CMV infections, esophagitis, colitis,                        hepatitis, lymphoma.                                              Ocular Conjunctivitis, keratitis, keratoconjunctivitis, uveitis,                          retinitis, chorioretinitis, CMV retinitis, iridocycliti s,                    vitreitis, choroiditis, papilledema, Kaposi's sarcoma,                        lymphoma, ocular palsies, conjunctival warts,                      pre-neoplastic and neoplastic diseases of the eye.                           CardiacMyocarditis, endocarditis, pericarditis.                               Pulmonary CMV pneumonitis, lymphoid interstitial pneumonitis.                 Nephroiogic HIV nephropathy, renal cell carcinoma, amyloidosis,                           uropathy.                                                         Rheumatologic Arthralgia, fibromyalgia, Reiter's syndrome, psoriatic                      arthritis, vasculitis.                                            Neurologic Dementia, viral meningitis, viral encephalitis, HIV                 encephalopathy, progressive multifocal                                        leukoencephalopathy, CNS lymphoma, peripheral and                             autonomic neuropathies.                                                      Psychiatric Dysphoric mood disorders, depression, depression                   associated with chronic diseases and medications, bipolar                     disorder, anxiety disorders, chronic fatigue syndrome,                        chronic pain, psychoses, substanee abuse disorders and                        drug addiction.                                                              GeneralLymphoma, metastatic lymphoma, Kaposi's sarcoma, wasting                           syndrome.                                                       __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________    Examples of neurological and psychiatric disorders that can be treated         with compounds described in this invention                                   __________________________________________________________________________    Neurological Disorders                                                         Migraine headaches                                                            Alzheimer's disease                                                           Parkinson's disease                                                           Pain disorders including algesia, hyperalgesia, acute and                     chronic pain, allodynia                                                       Chronic fatigue syndrome                                                      Amnesia                                                                       Psychiatric Disorders                                                         Dysphoric mood disorders                                                      Dysthymic disorder                                                            Depression including depression associated with chronic                       diseases and medications                                                      Manic depressive disorder                                                     Anxiety states including panic disorder and agoraphobia                       Post menstrual syndrome                                                       Obsessive-compulsive disorder, schizophrenia, chronic fatigue syndrome        Substance abuse and drug addiction                                           __________________________________________________________________________

                                      TABLE VII                                   __________________________________________________________________________    Diseases of the eye treatable with compounds described in this invention      __________________________________________________________________________    1. Diseases caused by viruses or associated with viral infections Disease     Virus                                                                         Blepharitis HSV, VZV, Vaccinia, HPV, molluscum contagiosum                                 Conjunctivitis HSV, VZV, EBV, adenovirus, vaccinia, variola,                 HPV,                                                                 molluscum contagiosum, influenza                                             Follicular c. Newcastle, measles, mumps, rubella, molluscum contagiosum       Hemorrhagic c. Enterovirus, coxsackie                                         Catarrhal c Rubella                                                           Keratitis HSV; VZV, EBV, Adenovirus, Vaccinia, Variola, HPV,                   molluscum contagiosum                                                        Keratoconjunctivitis HSV, VZV, EBV, Adenovirus, Vaccinia, Variola, HPV,        molluscum contagiosum                                                        Retinitis CMV                                                                 Uveitis HPV                                                                   Conjunctival warts HPV                                                        C. epithelial neoplasms HPV                                                 2. Ocularplastic diseases                                                       Benign tumors: Keratocanthoma, molluscum contagiosum, dermoid cysts,        neurofibroma,                                                                     neurofibromatosis, schwannoma (neurilemoma), pleiomorphic adenoma          Malignant tumors: Basal cell carcinoma, squamous cell carcinoma,             mucoepidermoid                                                                    carcinoma, melanorna, retinoblastoma, embryonal rhabdomyosarcoma,            meningioma, adenoid cystic carcinoma, lymphoid tumors of the orbit,           mesenchymal tumors (fibrous hystiocytoma) of the orbit, nasopharyngeal        carcinoma.                                                                  Vascular lesions: Hemangioma, lymphangioma.                                   3. Inflammatory/immunological ocular diseases                                 Acute allergic conjunctivitis and hypersensitivity reactions                  Drug-related inflammation and hypersensitivity reactions                      Chronic (vernal) conjunctivitis                                               Contact lens-associated conjunctivitis, e.g. giant papillary conjunctivit    is                                                                             Cojunctival ulceration, including ulceration associated with mucous          membrane                                                                          pemphigoid and the Steven's-Johnson syndrome, leading to progressive         fibrosis and scarring, cicatrization and symblepharon.                      4. Other lesions                                                              Retina: Macular degeneration, retinopathy, including diabetic r. and         hypertensive r.                                                                 Lens: Cataract, all etiologies includiiig rheumatological and collagen      vascular diseases                                                               Uvea: Ueitis, vitreitis, all etiologies, including UV radiation and         diabetes.                                                                     __________________________________________________________________________

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference into thespecification in their entirety for all purposes.

Although the invention has been described with reference to preferredembodiments and examples thereof, the scope of the present invention isnot limited only to those described embodiments. As will be apparent topersons skilled in the art, modifications and adaptations to theabove-described invention can be made without departing from the spiritand scope of the invention, which is defined and circumscribed by theappended claims.

What is claimed is:
 1. A compound of the formula ##STR17## wherein: Y isS;X is a member selected from the group consisting of O, S and NR⁶,wherein R⁶ is a member selected from the group consisting hydrogen andoptionally substituted (C₁ -C₁₀)alkyl; R¹, R², R³ and R⁴ are membersindependently selected from the group consisting of hydrogen, hydroxy,halogen, optionally substituted (C₁ -C₆)alkyl, optionally substituted(C₁ -C₂₀)alkoxy, (C₁ -C₆)alkylcarbonyl, (C₁ -C₂₀)alkenyl, R²⁴ R²³N(CH₂)_(x) CH(OH)(CH₂)_(y) O--, optionally substituted aroyl and aryl(C₁-C₁₀)alkylcarbonyl; R is a member selected from the group consisting ofhydrogen, phenyl, 3,4-dihydroxyphenyl and R¹¹, wherein R¹¹ is a memberselected from the group consisting of --A--NR¹³ R¹⁴, --CONHR¹⁵,--A--S--R¹⁶ and --COOR¹⁷, wherein A denotes a lower alkylene group; R¹³and R¹⁴ are members independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, cycloalkyl and a sulfur- and anitrogen-containing 5- or 6-membered heterocyclic ring, wherein saidheterocyclic ring may be optionally substituted by one or two hydroxylgroups, or, alternatively, R¹³ and R¹⁴ together with the nitrogen towhich they are bound form a pyrrolidine, piperidine or morpholine ring;R¹⁵ is a member selected from the group consisting of hydrogen andoptionally substituted (C₁ -C₆)alkyl; R¹⁶ is a member selected from thegroup consisting of (C₁ -C₆)alkyl and a sulfur- and nitrogen containing5- or 6-membered heterocyclic ring wherein said heterocyclic ring may beoptionally substituted by one or two hydroxyl groups, carboxyl groups,or (C₁ -C₆)alkoxycarbonyl groups; R¹⁷ is optionally substituted (C₁-C₆)alkyl; R²³ is a member selected from the group consisting ofhydrogen and optionally substituted (C₁ -C₆)alkyl; R²⁴ is a memberselected from the group consisting of phenyl, benzyl, and R²⁵ (CH₂)_(s)CH(T)(CH₂)_(k), or a heterocyclic ring having the formula ##STR18## oralternatively, together with R²³ and the nitrogen atom to which they arebound form a 5- or 6-membered heterocyclic ring having the formula##STR19## R²⁵ is either phenoxy or unsubstituted, monosubstituted, ordisubstituted Ar, wherein, Ar is a member selected from the groupconsisting of phenyl, pyridinyl, furanyl, thiophenyl, naphthyl, eachsubstituent of monosubstituted Ar is a member selected from the groupconsisting of hydroxy, (C₁ -C₆)alkoxy, and O(CH₂)_(r) CO₂ R²³, eachsubstituent of disubstituted Ar is independently hydroxy or (C₁-C₆)alkoxy, Q is a member selected from the group consisting of SO₂, S,or O; x is an integer from 1 to 5; y is an integer from 1 to 5; h is aninteger from 1 to 2; k is an integer from 1 to 7; r is an integer from 0to 2; s is a integer from 0 to 6; T is either hydrogen or OH; Z is amember of the group consisting of CH₂, O, NH, NCH₃, and ##STR20## q isan integer from 0 to 1; n is an integer from 0 to 5; t is an integerfrom 0 to 1; m is an integer from 0 to 2; p is an integer from 0 to 1; zis an integer from 0 to 1; provided that (1) at least one of x and y isone and (2) s plus k total no more than
 7. 2. A compound in accordancewith claim 1, wherein:Y is S; X is a member selected from the groupconsisting of O, S and NR⁶, wherein R⁶ a member selected from the groupconsisting hydrogen and optionally substituted (C₁ -C₆)alkyl; R is amember selected from the group consisting of hydrogen and3,4-dihydroxyphenyl; R¹ and R³ are each hydroxy; R² and R⁴ are eachhydrogen; q is an integer from 0 to 1; n is an integer from 0 to 5; t isan integer from 0 to 1; m is an integer from 0 to 2: p is an integerfrom 0 to 1; and z is
 0. 3. A compound in accordance with claim 2,whereinY is S; R is 3,4-dihydroxyphenyl; q is 1; n is 1 to 5; t is 0; mis 0; and p is
 0. 4. A compound in accordance with claim 3, whereinnis
 1. 5. A compound in accordance with claim 3, whereinn is
 2. 6. Acompound in accordance with claim 3, whereinn is
 3. 7. A compound inaccordance with claim 3, whereinn is
 4. 8. A compound in accordance withclaim 3, whereinn is
 5. 9. A compound in accordance with claim 2,whereinY is S; R is 3,4-dihydroxyphenyl; q is 0; n 1 to 5; t is 0; m is0; and p is
 0. 10. A compound in accordance with claim 9, whereinn is 2.11. A compound in accordance with claim 9, whereinn is
 3. 12. A compoundin accordance with claim 2, whereinR is 3,4-dihydroxyphenyl; q is 1; nis 2 t is 1; m is 2; and p is
 0. 13. A compound in accordance with claim12, whereinY is S; and X is
 0. 14. A compound in accordance with claim12, whereinY is S; and X is NR⁶, wherein R⁶ is ethyl.
 15. A compound inaccordance with claim 2, whereinR is H; q is 1; t is 0; n is 1 to 5; mis 0; and p is
 1. 16. A compound in accordance with claim 15, whereinnis
 1. 17. A compound in accordance with claim 15, whereinn is
 2. 18. Acompound in accordance with claim 15, whereinn is
 3. 19. A compound inaccordance with claim 15, whereinn is
 4. 20. A compound in accordancewith claim 15, whereinn is
 5. 21. A compound in accordance with claim 2,whereinR is H; q is 1; t is 1; n is 2; m is 2; and p is
 1. 22. Apharmaceutical composition comprising a compound of the compound of theformula ##STR21## wherein: Y is S;X is a member selected from the groupconsisting of O, S and NR⁶, wherein R⁶ is a member selected from thegroup consisting hydrogen and optionally substituted (C₁ -C₁₀)alkyl; R¹,R², R³ and R⁴ are members independently selected from the groupconsisting of hydrogen, hydroxy, halogen, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₁ -C₂₀)alkoxy, (C₁-C₆)alkylcarbonyl, (C₁ -C₂₀)alkenyl, R²⁴ R²³ N(CH₂)_(x) CH(OH)(CH₂)_(y)O--, optionally substituted aroyl and aryl(C₁ -C₁₀)alkylcarbonyl; R is amember selected from the group consisting of hydrogen, phenyl,3,4-dihydroxyphenyl and R¹¹, wherein R¹¹ is a member selected from thegroup consisting of --A--NR¹³ R¹⁴, --CONHR¹⁵, --A--S--R¹⁶ and --COOR⁷,wherein A denotes a lower alkylene group; R¹³ and R¹⁴ are membersindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, cycloalkyl and a sulfur- and a nitrogen-containing 5- or6-membered heterocyclic ring, wherein said heterocyclic ring may beoptionally substituted by one or two hydroxyl groups, or, alternatively,R¹³ and R¹⁴ together with the nitrogen to which they are bound form apyrrolidine, piperidine or morpholine ring; R¹⁵ is a member selectedfrom the group consisting of hydrogen and optionally substituted (C₁-C₆)alkyl; R¹⁶ is a member selected from the group consisting of (C₁-C₆)alkyl and a sulfur- and nitrogen containing 5- or 6-memberedheterocyclic ring wherein said heterocyclic ring may be optionallysubstituted by one or two hydroxyl groups, carboxyl groups, or (C₁-C₆)alkoxycarbonyl groups; R¹⁷ is optionally substituted (C₁ -C₆)alkyl;R²³ is a member selected from the group consisting of hydrogen andoptionally substituted (C₁ -C₆)alkyl; R²⁴ is a member selected from thegroup consisting of phenyl, benzyl, and R²⁵ (CH₂)_(s) CH(T)(CH₂)_(k), ora heterocyclic ring having the formula ##STR22## or alternatively,together with R²³ and the nitrogen atom to which they are bound form a5- or 6-membered heterocyclic ring having the formula ##STR23## R²⁵ iseither phenoxy or unsubstituted, monosubstituted, or disubstituted Ar,wherein, Ar is a member selected from the group consisting of phenyl,pyridinyl, furanyl, thiophenyl, naphthyl, each substituent ofmonosubstituted Ar is a member selected from the group consisting ofhydroxy, (C₁ -C₆)alkoxy, and O(CH₂)_(r) CO₂ R²³, each substituent ofdisubstituted Ar is independently hydroxy or (C₁ -C₆)alkoxy, Q is amember selected from the group consisting of SO₂, S, or O; x is aninteger from 1 to 5; y is an integer from 1 to 5; h is an integer from 1to 2; k is an integer from 1 to 7; r is an integer from 1 to 2; s is ainteger from 0 to 6; T is either hydrogen or OH; Z is a member of thegroup consisting of CH₂, O, NH, NCH₃, and ##STR24## q is an integer from0 to 1; n is an integer from 0 to 5; t is an integer from 0 to 1; m isan integer from 0 to 2; p is an integer from 0 to 1; z is an integerfrom 0 to 1; provided that (1) at least one of x and y is one and (2) splus k total no more than or a pharmaceutical acceptable salt or solvatethereof; and a pharmaceutical acceptable carrier.
 23. A composition inaccordance with claim 22, wherein:Y is S; X is a member selected fromthe group consisting of O, S and NR⁶, wherein R⁶ a member selected fromthe group consisting hydrogen and optionally substituted (C₁ -C₆)alkyl;R is a member selected from the group consisting of H and3,4-dihydroxyphenyl; R¹ and R³ are each hydroxy; R² and R⁴ are eachhydrogen; q is an integer from 0 to 1; n is an integer from 0 to 5; t isan integer from 0 to 1; m is an integer from 0 to 2; p is an integerfrom 0 to 1; and z is
 0. 24. A composition in accordance with claim 23,whereinY is S; R is 3,4-dihydroxyphenyl; q is 1; n is 1 to 5; t is 0; mis 0; and p is
 0. 25. A composition in accordance with claim 23,whereinY is S; R is 3,4-dihydroxyphenyl; q is 0; n is 1 to 5; t is 0; mis 0; and p is
 0. 26. A method of treating a PPARγ mediated disease,said method comprising administering a therapeutically effective amountof a compound of the formula ##STR25## wherein: Y is S;X is a memberselected from the group consisting of O, S and NR⁶, wherein R⁶ is amember selected from the group consisting hydrogen and optionallysubstituted (C₁ -C₁₀)alkyl; R¹, R², R³ and R⁴ are members independentlyselected from the group consisting of hydrogen, hydroxy, halogen,optionally substituted (C₁ -C₆)alkyl, optionally substituted (C₁-C₂₀)alkoxy, (C₁ -C₆)alkylcarbonyl, (C₁ -C₂₀)alkenyl, R²⁴ R²³ N(CH₂)_(x)CH(OH)(CH₂)_(y) O--, optionally substituted aroyl and aryl(C₁-C₁₀)alkylcarbonyl; R is a member selected from the group consisting ofhydrogen, phenyl, 3,4-dihydroxyphenyl and R¹¹, wherein R¹¹ is a memberselected from the group consisting of --A--NR¹³ R¹⁴, --CONHR¹⁵,--A--S--R¹⁶ and --COOR¹⁷, wherein A denotes a lower alkylene group; R¹³and R¹⁴ are members independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, cycloalkyl and a sulfur- and anitrogen-containing 5- or 6-membered heterocyclic ring, wherein saidheterocyclic ring may be optionally substituted by one or two hydroxylgroups, or, alternatively, R¹³ and R¹⁴ together with the nitrogen towhich they are bound form a pyrrolidine, piperidine or morpholine ring;R¹⁵ is a member selected from the group consisting of hydrogen andoptionally substituted (C₁ -C₆)alkyl; R¹⁶ is a member selected from thegroup consisting of (C₁ -C₆)alkyl and a sulfur- and nitrogen containing5- or 6-membered heterocyclic ring wherein said heterocyclic ring may beoptionally substituted by one or two hydroxyl groups, carboxyl groups,or (C₁ -C₆)alkoxycarbonyl groups; R¹⁷ is optionally substituted (C₁-C₆)alkyl; R²³ is a member selected from the group consisting ofhydrogen and optionally substituted (C₁ -C₆)alkyl; R²⁴ is a memberselected from the group consisting of phenyl, benzyl, and R²⁵ (CH₂)_(s)CH(T)(CH₂)_(k), or a heterocyclic ring having the formula ##STR26## oralternatively, together with R²³ and the nitrogen atom to which they arebound form a 5- or 6-membered heterocyclic ring having the formula##STR27## R²⁵ is either phenoxy or unsubstituted, monosubstituted, ordisubstituted Ar, wherein, Ar is a member selected from the groupconsisting of phenyl, pyridinyl, furanyl, thiophenyl, naphthyl, eachsubstituent of monosubstituted Ar is a member selected from the groupconsisting of hydroxy, (C₁ -C₆)alkoxy, and O(CH₂)_(r) CO₂ R²³, eachsubstituent of disubstituted Ar is independently hydroxy or (C₁-C₆)alkoxy, Q is a member selected from the group consisting of SO₂, S,or O; x is an integer from 1 to 5; y is an integer from 1 to 5; h is aninteger from 1 to 2; k is an integer from 1 to 7; r is an integer from 1to 2; s is a integer from 0 to 6; T is either hydrogen or OH; Z is amember of the group consisting of CH₂, O, NH, NCH₃, and ##STR28## q isan integer from 0 to 1; n is an integer from 0 to 5; t is an integerfrom 0 to 1; m is an integer from 0 to 2; p is an integer from 0 to 1; zis an integer from 0 to 1; provided that (1) at least one of x and y isone and (2) s plus k total no more than
 7. 27. A method in accordancewith claim 26, whereinY is S; X is a member selected from the groupconsisting of O, S and NR⁶, wherein R⁶ a member selected from the groupconsisting hydrogen and optionally substituted (C₁ -C₆)alkyl; R is amember selected from the group consisting of hydrogen and3,4-dihydroxyphenyl; R¹ and R³ are each hydroxy; R² and R⁴ are eachhydrogen; q is an integer from 0 to 1; n is an integer from 0 to 5; t isan integer from 0 to 1; m is an integer from 0 to 2; p is an integerfrom 0 to 1; and z is
 0. 28. A method in accordance with claim 27,whereinY is S; R is 3,4-dihydroxyphenyl; q is 1; n is 1 to 5; t is 0; mis 0; and p is
 0. 29. A method in accordance with claim 27, whereinY isS; R is 3,4-dihydroxyphenyl; q is 0; n is 1 to 5; t is 0; m is 0; and pis
 0. 30. A method of treating a PPARγ mediated disease, said methodcomprising administering in combination therapy, a therapeuticallyeffective amount of a compound of the formula ##STR29## wherein: Y isS;X is a member selected from the group consisting of O, S and NR⁶,wherein R⁶ is a member selected from the group consisting hydrogen andoptionally substituted (C₁ -C₁₀)alkyl; R¹, R², R³ and R⁴ are membersindependently selected from the group consisting of hydrogen, hydroxy,halogen, optionally substituted (C₁ -C₆)alkyl, optionally substituted(C₁ -C₂₀)alkoxy, (C₁ -C₆)alkylcarbonyl, (C₁ -C₂₀)alkenyl, R²⁴ R²³N(CH₂)_(x) CH(OH)(CH₂)_(y) O--, optionally substituted aroyl and aryl(C₁-C₁₀)alkylcarbonyl; R is a member selected from the group consisting ofhydrogen, phenyl, 3,4-dihydroxyphenyl and R¹¹, wherein R¹¹ is a memberselected from the group consisting of --A--NR¹³ R¹⁴, --CONHR¹⁵,--A--S--R¹⁶ and --COOR¹⁷, wherein A denotes a lower alkylene group; R¹³and R¹⁴ are members independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, cycloalkyl and a sulfur- and anitrogen-containing 5- or 6-membered heterocyclic ring, wherein saidheterocyclic ring may be optionally substituted by one or two hydroxylgroups, or, alternatively, R¹³ and R¹⁴ together with the nitrogen towhich they are bound form a pyrrolidine, piperidine or morpholine ring;R¹⁵ is a member selected from the group consisting of hydrogen andoptionally substituted (C₁ -C₆)alkyl; R¹⁶ is a member selected from thegroup consisting of(C₁ -C₆)alkyl and a sulfur- and nitrogen containing5- or 6-membered heterocyclic ring wherein said heterocyclic ring may beoptionally substituted by one or two hydroxyl groups, carboxyl groups,or (C₁ -C₆)alkoxycarbonyl groups; R¹⁷ is optionally substituted (C₁-C₆)alkyl; R²³ is a member selected from the group consisting ofhydrogen and optionally substituted (C₁ -C₆)alkyl; R²⁴ is a memberselected from the group consisting of phenyl, benzyl, and R²⁵ (CH₂)_(s)CH(T)(CH₂)_(k), or a heterocyclic ring having the formula ##STR30## oralternatively, together with R²³ and the nitrogen atom to which they arebound form a 5- or 6-membered heterocyclic ring having the formula##STR31## R²⁵ is either phenoxy or unsubstituted, monosubstituted, ordisubstituted Ar, wherein, Ar is a member selected from the groupconsisting of phenyl, pyridinyl, furanyl, thiophenyl, naphthyl, eachsubstituent of monosubstituted Ar is a member selected from the groupconsisting of hydroxy, (C₁ -C₆)alkoxy, and O(CH₂)_(r) CO₂ R²³, eachsubstituent of disubstituted Ar is independently hydroxy or (C₁-C₆)alkoxy, Q is a member selected from the group consisting of SO₂, S,or O; x is an integer from 1 to 5; y is an integer from 1 to 5; h is aninteger from 1 to 2; k is an integer from 1 to 7; r is an integer from 1to 2; s is a integer from 0 to 6; T is either hydrogen or OH; Z is amember of the group consisting of CH₂, O, NH, NCH₃, and ##STR32## q isan integer from 0 to 1; n is an integer from 0 to 5; t is an integerfrom 0 to 1; m is an integer from 0 to 2; p is an integer from 0 to 1; zis an integer from 0 to 1; provided that (1) at least one of x and y isone and (2) s plus k total no more than 7; and a member selected fromthe group consisting of a drug that bind to or modifies activity of avitamin D receptor, a retinoid X receptor, or a retinoic acid receptor.31. A method in accordance with claim 30, wherein said combination drugis a member selected from the group consisting of 9-cis-rctinoic acid,13-cis-retinoic acid, all-trans-retinoic acid, tazarotene, Targretin,1,25-dihydroxy-vitamin, calcipotriene, LG100268 and TTNPB.